JP2008179612A - Method of treatment of obesity - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an MTP inhibitor effective for treatment of obesity or related eating disorders and/or reducing food consumption. <P>SOLUTION: In a treatment of a subject suffering from obesity or related eating disorders and/or reducing food consumption, a therapeutically effective amount of an MTP inhibitor, for example, dirlotapide or (S)-N-ä2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[(4'-trifluoromethyl)[1,1'-biphenyl]-2-carboxyamido]-1H-indole-2-carboxamide in conjunction with an increased-fat diet, is given to the subject. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to the treatment of obesity or related eating disorders and / or reduced food consumption using MTP inhibitors in conjunction with a high fat diet.

  Obesity has become a major social concern due to the increased number of patients and health risks. Obesity is not only subject to social academic and work discrimination, but obesity adversely affects the quality of life of people and animals, including limited exercise capacity and reduced physical endurance.

Inhibitors of microsomal triglyceride transfer protein (MTP) and / or Apo B (Apo
B) Secretions are useful for reducing mammalian food intake (Patent Document 1), reducing intestinal fat absorption (Patent Document 2), and treating obesity and related diseases (for example, Patent Documents 3 to 6). It is.

  However, Patent Document 7 reports that MTP inhibitors may show side effects such as hepatotoxicity.

  In addition, the present inventors have discovered that administration of the MTP inhibitor dillrotapide disclosed in Patent Document 3 according to a conventional treatment regimen may cause vomiting.

European Patent Application Publication No. 1,099,438 A2 European Patent Application Publication No. 1,099,439A2 WO2003 / 002533 WO2005 / 046644 WO2005 / 080373 US Pat. No. 6,066,653 WO2005 / 087234

  Therefore, development of a more effective treatment method using an MTP inhibitor for obesity or related eating disorders and / or food consumption reduction is desired.

  The present invention relates to a method of treating a subject exhibiting symptoms of obesity or an associated eating disorder and / or reduced food intake, wherein the subject is provided with a therapeutically effective amount of an MTP inhibitor together with a high fat diet. provide.

  The present invention also provides a method of using an MTP inhibitor in the manufacture of a medicament for treating a subject exhibiting symptoms of obesity or an associated eating disorder and / or reduced food intake, comprising a therapeutically effective amount of MTP A method of providing an inhibitor to a subject with a high fat diet is provided.

  Furthermore, the present invention is a method for treating a subject exhibiting symptoms of obesity or related eating disorders and / or reduced food consumption, wherein a therapeutically effective amount of an MTP inhibitor is administered to the subject together with a high fat diet. Later, an optional large amount of MTP inhibitor is administered at least once, followed by optional subsequent weight maintenance / management or retraining.

  Furthermore, the present invention relates to the use of an MTP inhibitor in the manufacture of a medicament for treating a subject exhibiting symptoms of obesity or an associated eating disorder and / or reduced food intake, comprising a therapeutically effective amount of the MTP inhibitor Is administered to the subject along with a high fat diet, and optionally a large amount of MTP inhibitor is administered at least once, followed by optional weight maintenance / management or retraining.

  The invention further provides a method of treating a subject exhibiting symptoms of obesity or an associated eating disorder and / or reduced food intake, wherein a therapeutically effective amount of an MTP inhibitor is provided to the subject together with a high fat diet, Methods are provided wherein the therapeutically effective amount of the MTP inhibitor is less than a conventional therapeutic regimen.

  The present invention further provides a method for improving the weight loss rate of a subject exhibiting symptoms of obesity or an eating disorder associated therewith, wherein the subject is provided with a therapeutically effective amount of an MTP inhibitor together with a high fat diet.

  The present invention further provides a method of treating a subject exhibiting symptoms of obesity or related eating disorders and / or reduced food intake, wherein an initial amount of an MTP inhibitor is provided to the subject together with a high fat diet, The initial amount is an amount effective for improving obesity and disorders, and is a sufficiently small amount from the viewpoint of reducing side effects due to the administration of the MTP inhibitor. Provided is a method of administering an MTP inhibitor at least once, followed by optional weight maintenance / management or retraining.

  The present invention further provides a method of treating a subject exhibiting symptoms of obesity or related eating disorders and / or reduced food intake, wherein an initial amount of an MTP inhibitor is provided to the subject together with a high fat diet, The initial dose is from 0.025 to 0.30 mg / kg / day, and after this administration, optionally a large amount of MTP inhibitor is administered at least once, followed by optional weight maintenance / management or retraining. Provide a method.

  The present invention further provides a method of inhibiting MTP in a subject in need of MTP inhibition, wherein a therapeutically effective amount of an MTP inhibitor is provided to the subject along with a high fat diet.

  Furthermore, the present invention provides a method for treating a subject exhibiting symptoms of obesity or a related eating disorder and / or reduced food intake, or a method for inhibiting MTP in a subject in need of MTP inhibition, which is therapeutically effective. An amount of MTP inhibitor is provided to the subject along with a high fat diet, wherein the MTP inhibitor is administered in combination with at least one additional agent (such as an anti-obesity agent).

  Furthermore, the present invention provides a method for managing the weight of a subject, wherein the subject is provided with an amount of an MTP inhibitor effective for weight management together with a high fat diet. The MTP inhibitor may be used alone or in combination with at least one additional drug, preferably an anti-obesity drug.

  In some embodiments, the MTP inhibitor is dirlotapide ((S) -N- {2- [benzyl (methyl) amino] -2-oxo-1-phenylethyl} -1-methyl-5- [4'-tri Fluoromethyl) [1,1′-biphenyl] -2-carboxamido] -1H-indole-2-carboxamide).

Definitions Usually human obesity and overweight are defined by the body mass index (BMI). BMI is an index related to all body fats and is used as an index for measuring the risk of disease. BMI (kg / m ² ) is obtained by dividing body weight (kilogram) by height (m) squared. Typically, BMI may overweight of 25~29.9kg / ^{m 2,} BMI defines the case of 30kg / ^{m 2} or more and obesity. Obesity in dogs and cats is usually defined by a body condition score (BCS), with Purina's 9-level rating being 8 or more overweight, 6 or more being overweight, and Hill's 5-level rating. 5 or more is obese, 4 or more is overweight. Purina's 9-point rating is Laflamme DP, Body Condition Scoring and Weight Maintenance, Proceedings of North American Veterinary Conference (Proceedings of North American Veterinary Conference), January, 16-21, 1993, Orlando, Florida, 290-291, and Laflamme DP, Kealy RD, Schmidt DA, Estimate of Body. • Fat by Body Composition Score, Journal of Veterinary Internal Medicine, 1994, vol. 8, page 154.

  It should be understood that the treatment of obesity described above and below also encompasses the treatment of overweight.

  “Pharmaceutically acceptable” means that a substance or composition is chemically and / or toxicologically compatible with other ingredients in the formulation and / or with the mammal being treated by the formulation. It shows that.

  “Therapeutically effective amount” means (i) treating or preventing a particular disease, illness or disorder, (ii) reducing, ameliorating or eliminating one or more symptoms of a particular disease, illness or disorder, Alternatively (iii) means the amount of a compound that prevents or delays (eg, reduces food intake or appetite) the onset of one or more symptoms of a particular disease, condition or disorder.

  The “subject” or “animal” may be any human blood, as well as any warm-blooded animal having a homeostasis mechanism of the animal kingdom, including mammals (companion animals, zoo animals, food animals, etc.) and birds. Examples of pet animals include canines (dogs, etc.), cats (cats, etc.), and horses. Examples of food animals include pigs, cows, sheep, and poultry. This animal is preferably a mammal. The mammal is preferably a human, a pet animal, or an edible animal, and more preferably a human or a canine animal (cat, dog, etc.). The canine animal is, for example, a cat, and preferably a dog.

  “Treatment” includes both prophylactic and palliative treatment.

In practicing the method of the present invention, the MTP inhibitor preferably acts in the intestine and is preferably intestinal selective. In the present invention, the term “selectivity” is used for a greater effect of the compound in the first analysis than in the second analysis. In this embodiment, a first analysis is performed on the ability of the compound to inhibit intestinal fat absorption, and a second analysis is performed on the ability to reduce serum triglycerides. In a preferred embodiment, in the intestinal fat absorption assay, the dose at which the compound exhibits 25% fat absorption inhibition (ED ₂₅ ) is examined, thereby measuring the ability to inhibit intestinal fat absorption. If the compound has a greater effect, a lower absolute value (numerical value) of ED ₂₅ is obtained. In another preferred embodiment, in serum triglyceride analysis, the compound's ED ₂₅ is examined to determine the ability of the compound to reduce serum triglycerides. Again, if the compound has a greater serum triglyceride reducing effect, a lower absolute value (numerical value) of ED ₂₅ is obtained. The present invention should be understood to encompass any assay for determining the ability of a compound to inhibit intestinal fat absorption or reduce serum triglycerides. Examples of suitable analyzes include those described in WO 03/002533.

  By controlling the solubility of the inhibitor in the intestinal tract and / or the release of the inhibitor from the formulation, or increasing the amount of lipid (fat) in the intestinal tract (ie, increasing the amount of fat in the food given together) The above intestinal selectivity can be obtained.

  The Applicant has found that MTP inhibitors are effective as anti-obesity agents when taken with any meal, but their effectiveness as anti-obesity agents is significantly improved when taken with a high fat diet. . That is, it was discovered that when a subject is fed a high fat diet instead of a low fat diet, weight loss can be achieved with a small amount of MTP inhibitor. Giving an MTP inhibitor with a high fat diet increases the rate of weight loss. Furthermore, when the MTP inhibitor is given with a high fat diet, food intake is significantly reduced.

  As used herein, the term “high fat meal” and similar terms mean a meal having a fat content of about 10% or more based on the amount of air-dried product.

  “Amount of air-dried product” indicates the amount of the above food in an air-dried state, and usually dry dog food contains about 10% of water. Thus, for example, “the fat content based on the amount of the air dried product is 10%” is equivalent to “the fat content based on the amount of the dried product is about 11%”. A fat content based on 15% "would be equivalent to a fat content based on the amount of dry matter of about 16.7%.

  Therefore, the high fat diet used in the present invention is a normal fat diet or a controlled diet (for example, a fat content based on the amount of air-dried product is 10 to 17%), a high fat diet, an active diet, or a functional diet (for example, air). The conventional pet food (dog food etc.) etc. which are marketed as fat content based on the quantity of a dry substance may be 18% or more.

  Alternatively, a high fat diet may be defined by the ratio of energy by fat to total metabolic energy (Kcal). For example, the term “high fat diet” or similar terms used in the present invention means a meal in which the ratio of calories due to fat to total calories is about 24% or more (eg, about 34% or more, about 45% or more). . Therefore, the high fat diet used in the present invention is a normal fat diet or a management diet (for example, the ratio of calories by fat to the total calories is about 24 to 33%), a high fat diet, an active diet, or a functional diet (for example, total calories The conventional pet food (dog food etc.) etc. etc. which are marketed as the ratio of the calorie by the fat to about 34-50% may be sufficient.

  In one particular example, the term “high fat diet” or similar terms used in the present invention means a diet having a fat content of about 15% or more based on the amount of air-dried product. In another example, the term “high fat diet” or similar terms used in the present invention means a diet in which the ratio of calories derived from fat to total calories is about 45% or more.

MTP inhibitors used in the present invention are known in the art. Suitable MTP inhibitors include U.S. Pat. Nos. 4,453,913, 4,473,425, 4,491,589, 4,540,458, and 4,962. 115, 5,057,525, 5,137,896, 5,286,647, 5,521,186, 5,595,872, 5,646,162, 5,684,014, 5,693,650, 5,712,279, 5,714,494, 5,721, No. 279, No. 5,739,135, No. 5,747,505, No. 5,750,783, No. 5,760,246, No. 5,789,197, No. No. 5,811,429, No. 5,827,875, No. 5,837,733, No. 5, 49,751, No. 5,883,099, No. 5,883,109, No. 5,885,983, No. 5,892,114, No. 5,919,795, 5,922,718, 5,925,646, 5,929,075, 5,929,091, 5,935,984, 5,952 No. 5,498, No. 5,962,440, No. 5,965,577, No. 5,968,950, No. 5,998,623, No. 6,025,378, No. 6,034,098, 6,034,115, 6,051,229, 6,051,387, 6,051,693, 6,057, No. 339, No. 6,066,650, No. 6,066,653, No. 6,114,341 6,121,283, 6,191,157, 6,194,424, 6,197,798, 6,197,972, 6,200 971, 6,235,730, 6,235,770, 6,245,775, 6,255,330, 6,265,431, 6,281,228, 6,288,234, 6,329,360, 6,342,245, 6,369,075, 6,417, No. 362, No. 6,451,802, No. 6,479,503, No. 6,492,365, No. 6,583,144, No. 6,617,325, No. 6,713,489, 6,720,351, 6,774,236, 6,777, No. 414 and No. 6,878,724:
US Patent Publication Nos. 2002/028940, 2002/032238, 2002/055635, 2002/132806, 2002/147209, 2003/149073, 2003/073836 No. 2003/105093, No. 2003/114442, No. 2003/0162788, No. 2003/166590, No. 2003/1666637, No. 2003/181714, No. 2004/009988, No. 2004/014971, No. 2004/024215, No. 2004/034028, No. 2004/044008, No. 2004/058903, No. 2004/102490, No. 2004/157866, and 2005/234 99 issue:
International Publications WO96 / 262205, WO98 / 016526, WO98 / 031366, WO99 / 55313, WO00 / 005201, WO01 / 000183, WO01 / 000184, WO01 / 000189, WO01 / 005767, WO01 / 012601 No., WO01 / 014355, WO01 / 021604, WO01 / 053260, WO01 / 074817, WO01 / 077077, WO02 / 014276, WO02 / 014277, WO02 / 081460, WO02 / 083658, WO04 / 017969 No. and WO05 / 080373:
And compounds described in JP-A Nos. 2002-212179 (14212179) and 2002-220345 (14220345).

A review of Apo B / MTP inhibitors includes Williams, SJ and JD Best, Expert Opinion on Therapeutic Patents
Opinion Therapeutic Patents), 13 (4), 479-488 (2003). For a method of identifying active MTP inhibitors, see Chang, G. et al., “Microsomal Triglyceride Transfer Protein (MTP) Inhibitors: Discovery of Clinically Active Inhibitors Using High. Throughput screening and parallel synthesis paradigm (microsomal triglyceride transfer protein (MTP) inhibitors: Discovery
of clinically active inhibitors using high-throughput screening and parallel
synthesis paradigms) ", Current Opinion in Drug Discovery & Development, 5 (4), 562-570 (2002). All of the above patents, patent applications, and literature are included in the disclosure by reference.

  As an example of a preferable enteric action MTP inhibitor used in the present invention, it can be prepared by the method described in US Pat. No. 6,720,351 ((S) —N- {2- [benzyl (methyl) amino] -2-oxo-1-phenylethyl} -1-methyl-5- [4′-trifluoromethyl) [1,1′-biphenyl] -2-carboxamide] -1H-indole-2-carboxamide) and 1 -Methyl-5-[(4'-trifluoromethyl-biphenyl-2-carbonyl) -amino] -1H-indole-2-carboxylic acid (carbamoyl-phenyl-methyl) -amide; US Patent Publication No. 2005/0234099 (S) -2-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -quinoline-6-cal Acid (pentylcarbamoyl-phenyl-methyl) -amide, (S) -2-[(4′-tert-butyl-biphenyl-2-carbonyl) -amino] -quinoline-6-carboxylic acid {[(4-fluoro -Benzyl) -methyl-carbamoyl] -phenyl-methyl} -amide, (S) -2-[(4'-tert-butyl-biphenyl-2-carbonyl) -amino] -quinoline-6-carboxylic acid [(4 -Fluoro-benzylcarbamoyl) -phenyl-methyl] -amide, and (S) -2-[(4'-isopropoxy-biphenyl-2-carbonyl) -amino] -quinoline-6-carboxylic acid {[(4- Fluoro-benzyl) -methyl-carbamoyl] -phenyl-methyl} -amide; U.S. Pat. Nos. 5,521,186 and 5,929,075. (−)-4- [4- [4- [4-[[(2S, 4R) -2- (4-chlorophenyl) -2-[[(()), known as mitrapapide or R103757, which can be prepared by the method described in 4-methyl-4H-1,2,4-triazol-3-yl) sulfanyl] methyl-1,3-dioxolan-4-yl] methoxy] phenyl] piperazin-1-yl] phenyl] -2- (1R) -1 -methylpropyl] -2,4-dihydro-3H-1,2,4-triazol-3-one; Implicitapide (BAY 13-9952) which can be prepared by the method described in US Pat. No. 6,265,431; It can be prepared by the method described in US Pat. No. 6,878,724 and has the following formula:

As well as (4′-trifluoromethyl-biphenyl-2-carboxylic acid [2- (2H- [1,2,4] triazol-3-ylmethyl) -1,2,3,4-tetrahydro -Isoquinolin-6-yl] amide). More preferred MTP inhibitors are dirlotapide, mitrapapide, (S) -2-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -quinoline-6-carboxylic acid (pentylcarbamoyl-phenyl-methyl) -Amide, (S) -2-[(4'-tert-butyl-biphenyl-2-carbonyl) -amino] -quinoline-6-carboxylic acid {[(4-fluoro-benzyl) -methyl-carbamoyl] -phenyl -Methyl} -amide, (S) -2-[(4′-tert-butyl-biphenyl-2-carbonyl) -amino] -quinoline-6-carboxylic acid [(4-fluoro-benzylcarbamoyl) -phenyl-methyl ] -Amide, (S) -2-[(4'-isopropoxy-biphenyl-2-carbonyl) -amino] -quinoline- -Carboxylic acid {[(4-fluoro-benzyl) -methyl-carbamoyl] -phenyl-methyl} -amide, R256918, and (4'-trifluoromethyl-biphenyl-2-carboxylic acid [2- (2H- [1 , 2,4] triazol-3-ylmethyl) -1,2,3,4-tetrahydro-isoquinolin-6-yl] amide).

  The MTP inhibitor used in the method of the present invention is preferably (4′-trifluoromethyl-biphenyl-2-carboxylic acid [2- (2H- [1,2,4] triazol-3-ylmethyl) -1,2 , 3,4-Tetrahydro-isoquinolin-6-yl] amide, more preferably dillrotapid.

  Conventionally, when the intestinal action MTPi is used in humans, the daily dose is usually about 0.05 mg to about 50 mg, preferably about 0.5 mg to about 30 mg, more preferably about 0.5 mg to about 20 mg, and most preferably about 1.0 mg to about 15 mg. When using it for animals other than a human, those skilled in the art can adjust dosage according to the body weight of an animal. Depending on the condition, MTPi may be administered in combination with a hepatic fat-reducing drug (fibrates, PPAR-alpha agonists, etc.) (Japanese Patent Application Laid-Open No. 2002-220345 (Japanese Patent Application No. 2001-015602) Agents "), Kersten, S.," Peroxisome Proliferator Activated Receptors and Obesity ", European Journal of Pharmaceutical Sciences (European Journal) of Pharmaceutical Sciences), 440, 223-234 (2002), etc.).

  In certain embodiments, the dosage of the MTP inhibitor is increased. Use first dose level (initial dose level) and second dose level, use first, second, and third dose levels, first, second, third, and fourth doses Levels may be used, first, second, third, fourth, and fifth dosage levels may be used, or a sixth dosage level or additional dosage levels may be used to increase the dosage.

  It may be increased by 10%, 20%, 25%, 50%, 100%, or 300% from the initial dosage level to the next dosage level. If the initial dose level is increased by 100%, the next dose level will be twice the initial dose level. If the initial dose level is increased by 300%, the next dose level will be four times the initial dose level. The initial dosage level may be increased by 25%, 50%, or 100%, preferably increased by 50% or 100% (eg, 100%).

  The first dose level may be 0.025 to 0.30 mg / kg / day, for example, 0.025 to 0.10 mg / kg / day (such as about 0.05 or 0.10 mg / kg / day). Yes, preferably about 0.05 mg / kg / day.

  The second dose level may be 100% greater than the first dose level (0.05 to 0.6 mg / kg / day), for example 0.05 to 0.2 mg / kg / day (about 0.05). 10 or 0.2 mg / kg / day), preferably about 0.10 mg / kg / day.

  The third dose level may be 100% greater than the second dose level (0.10-1.2 mg / kg / day), for example, 0.10-0.4 mg / kg / day (about 0.1. 2 or 0.4 mg / kg / day, etc.), and preferably about 0.2 mg / kg / day.

  The fourth dosage level may be 50% greater than the third dosage level (0.15-0.9 mg / kg / day), for example 0.15-0.6 mg / kg / day (approximately 0.1. 3 or 0.6 mg / kg / day, etc.), and preferably about 0.3 mg / kg / day.

  Thereafter, it is preferred to increase by 50% from the fourth dosage level to the fifth, sixth and further dosage levels.

  When the MTP inhibitor is dirlotapide, the first dosage level may be 0.025 to 0.10 mg / kg / day, such as about 0.05 or 0.10 mg / kg / day, preferably about 0.05 mg / kg / day. The second dose level may be 100% greater than the first dose level (0.05 to 0.2 mg / kg / day), for example about 0.10 or 0.2 mg / kg / day, Preferably it is about 0.10 mg / kg / day. The third dose level may be 100% greater than the second dose level (0.10-0.4 mg / kg / day), for example about 0.2 or 0.4 mg / kg / day, Preferably, it is about 0.2 mg / kg / day. The fourth dose level may be 50% greater than the third dose level (0.15-0.6 mg / kg / day), for example about 0.3 or 0.6 mg / kg / day, Preferably, it is about 0.3 mg / kg / day. Thereafter, it is preferred to increase by 50% from the fourth dosage level to the fifth, sixth and further dosage levels. In certain embodiments, the subject is administered about 1 to 4 weeks at each dosage level, eg, increasing the dosage level every week, every two weeks, or every month. For example, the first dose level (0.05 mg / kg / day, etc.) is administered for about 14 days, the second dose level (0.01 mg / kg / day, etc.) is administered for about 14 days, and the third dose is administered. It is administered for 1 month at a level (0.2 mg / kg / day, etc.), and thereafter the dose is increased every month.

  For example, when dirlotapide is used as an MTP inhibitor and administered to a dog, the initial dose may be 0.05 mg / kg / day. After treatment for 2 weeks, the dose may be administered for another 2 weeks at a dose level (0.10 mg / kg / day) twice the initial dose. Following this 4-week initial treatment, the dog is weighed and the dose adjusted, for example, according to the following guidelines. Determine the rate of weight loss at the end of each month's treatment. If the body weight has decreased by more than 3% compared to the previous month's measurement (if the body weight has decreased by more than 0.1% per day), maintain that dose level. If the weight loss rate from the previous month's weighing was less than 3%, the dose level is increased regardless of the dog's weight at that time. During the first level increase, the dose level may be increased by 100% (may be doubled), and when the level is increased thereafter, the dose level is increased by 50% to the maximum dose level (1 mg / kg body weight). May be increased. Such adjustment of the administration level may be continued until the target body weight at the start of treatment is obtained.

  If the weight loss rate from the previous month was 12% or more, the dosage level may be reduced by 25%.

  An average of about 18-20% weight loss can be expected with 6 months of weight loss treatment.

  This initial weight loss phase may be performed for several months, for example, about 4 months (16 weeks) to 6 months, or about 112 to 196 days. Alternatively, the initial weight loss phase may be performed until a target weight is obtained or until a specific body condition score (BCS), eg, 5 is reached.

  The weight maintenance / management or retraining phase may be carried out for several months, for example about 3 months (ie about 12 weeks) or 84 days. If the patient's weight is reduced or increased too much (eg, greater than 5%) compared to the beginning of this phase, the dose may be reduced by 50% or increased by 100% during the retraining phase.

  As described above, when the target weight is reached, the weight maintenance / management or retraining phase can begin. During this weight maintenance / management or retraining phase, optimal food intake and physical activity are established. Administration of the MTP inhibitor should continue during the weight maintenance / management or retraining phase until the food intake and physical activity necessary to stabilize the target body weight are established.

  For example, when dirlotapide is used as a MTP inhibitor and administered to a dog, the dose may be adjusted as follows at the stage of weight maintenance / management or retraining.

First dose adjustment During the last month of the weight loss phase, if the dog's body weight is reduced by more than 1% per week, the dose is reduced by 50%.
If the dog's weight is reduced by 0 to 1%, the dose is kept the same.
If the dog gains weight, the dosage is increased by 50%.

Subsequent dose adjustment Over the next few months, the dose is increased or decreased by 25% to maintain a constant body weight.
If the dog's weight is in the range of -5% to + 5% of the last weight in the weight loss phase, the dose is kept the same.
If the dog's weight is reduced by more than 5%, the dosage is reduced by 25%.
If the dog's weight increases by 5% or more, the dosage is increased by 25%. The daily dose should not exceed 1 mg / kg based on the current weight of the dog.

  If administration is discontinued, daily feeding and physical activity established during the weight maintenance / management or retraining phase should continue.

  “Reduction of side effects from administration of MTP inhibitors” or similar terms refers to conventional treatment regimens (eg, at high initial doses, without a gradual increase in dose, and together providing a high fat diet) Without) means an improvement or elimination of undesirable side effects resulting from the administration of an MTP inhibitor. Examples of side effects include vomiting, diarrhea, lethargy, loss of appetite, and anorexia. Side effects are, for example, vomiting, diarrhea, lethargy etc., especially vomiting.

In the method of the present invention, at least one additional drug may be administered. Examples of suitable additional agents include other anti-obesity agents such as cannabinoid 1 (CB-1) antagonists (such as rimonabant), 11β-hydroxysteroid dehydrogenase 1 (11β-HSD type 1) inhibitors, peptide YY (PYY ) And PYY agonists (PYY _3-36 , analogs and derivatives thereof), MCR-4 agonists, cholecystokinin A (CCK-A) agonists, monoamine reuptake inhibitors (sibutramine, etc.), sympathetic-like Agonist, β ₃ adrenergic receptor agonist, dopamine receptor agonist (bromocriptine, etc.), melanocyte stimulating hormone receptor analog, 5HT2c receptor agonist, melanin-concentrating hormone antagonist, leptin (OB protein), leptin analog Body, leptin receptor agonist, galanin antagonist, lipase inhibitor (tetrahydrolipstatin) Ie, orlistat), appetite suppressant (bombesin agonist, etc.), neuropeptide Y receptor antagonist (NPY-Y5 receptor antagonist, etc.), thyroid hormone agent, dehydroepiandrosterone and analogs thereof, glucocorticoid receptor Body agonists and antagonists, orexin receptor antagonists, glucagon-like peptide 1 receptor agonists, ciliary neurotrophic factor (Regeneron Pharmaceuticals, Inc., Tarrytown, NY) and Proctor -Axokine (Axokine (registered trademark), etc.) manufactured by Procter & Gamble Company (Cincinnati, Ohio), human-agglutinin protein (AGRP) inhibitors, ghrelin receptor antagonists, histamine 3 receptor antagonists and Inverse agonists, neuromedin U receptor agonists, etc. It is.

  Other examples of suitable additional agents include lipid modifying compounds such as HMG-CoA reductase inhibitors, cholesterol absorption inhibitors, ezetimides, squalene synthetase inhibitors, fibrates, bile acid inhibitors, statins, probucols and the like Examples thereof include niacin, niacin derivatives, PPAR alpha agonists, PPAR gamma agonists, thiazolidinediones, and cholesterol ester transfer protein (CETP) inhibitors.

  Other examples of suitable additional agents include LDL-cholesterol lowering drugs, triglyceride lowering drugs, HMG-CoA reductase inhibitors, HMG-CoA synthase inhibitors, HMG-CoA reductase gene expression inhibitors, squalene synthetase inhibitors, Squalin epoxidase inhibitor, squalin cyclase inhibitor, squalin epoxidase / cyclase combined inhibitor, cholesterol synthesis inhibitor, cholesterol absorption inhibitor (Zetia (registered trademark) (ezetimibe), etc.), CETP inhibitor, PPAR modifiers, other cholesterol-lowering drugs (such as fibrates), ion exchange resins, antioxidants, ACAT inhibitors, bile acid inhibitors and the like. Further, other pharmaceuticals that can be used in combination with the present invention include bile acid reuptake inhibitors, ileal bile acid transporter inhibitors, ACC inhibitors, antihypertensive drugs (Norvasc ™, etc.), diuresis Agents, garlic extract, bile acid inhibitors, antibiotics, anti-diabetic agents, and anti-inflammatory agents (such as aspirin). Anti-inflammatory agents that inhibit cyclooxygenase 2 (Cox-2) are preferred over cyclooxygenase 1 (Cox-1). For example, celecoxib (US Pat. No. 5,466,823), valdecoxib (US Pat. No. 5, 633,272), parecoxib (US Pat. No. 5,932,598), delacoxib (CAS RN 169590-41-4), lefecoxib (CAS RN 162011-90-7), etoroxib (CAS RN 202409-33-4) ), Luminacoxib (CAS RN 220991-20-8), and carprofen (CAS RN 53716-49-7).

  Further examples of suitable additional agents include natural products that can reduce plasma cholesterol levels. Such natural products are usually referred to as dietary supplements, examples of which include garlic extract, hoodia extract, and niacin.

  In general, the dosage of the additional drug will depend on several factors such as the health of the subject being treated, the degree of treatment desired, the nature and type of other treatments at the same time, the frequency of treatment, and the effect of the desired treatment. decide. The dosage of the additional drug is usually about 0.001 mg to about 100 mg per kg body weight per day, preferably about 0.1 mg to about 10 mg. However, it is necessary to change the normal dose range according to the age and weight of the subject to be treated, the administration route, the specific anti-obesity drug to be administered, and the like. One skilled in the art can determine the dosage range and optimal dosage for the patient to practice the present invention.

  The additional active agent may be administered based on a conventional therapeutic regimen. Also, the dose of additional active agent may be gradually increased.

  In the treatment method of the present invention, an MTP inhibitor and an additional agent (referred to as a “complex”) may be administered to a subject in need of treatment, preferably in the form of a pharmaceutical preparation. MTP inhibitors and other medications (such as other anti-obesity agents) may be administered separately or in the form of pharmaceutical preparations containing both. Usually, these are preferably administered orally. When administering an MTP inhibitor and another pharmaceutical agent, these may be administered sequentially or simultaneously, and it is usually preferable to administer them sequentially. When administered sequentially, each drug may be administered in any order. Usually, it is preferable to administer each drug orally. It is particularly preferred to administer these drugs simultaneously orally. When administered sequentially, the method of administering the MTP inhibitor and the additional agent may be the same or different.

  In the method of the present invention, the MTP inhibitor or the complex is preferably administered in the form of a pharmaceutical preparation. Each agent may be administered separately or together in any conventional manner. Administration methods include oral administration, rectal administration, transdermal administration, parenteral administration (intravenous administration, intramuscular administration, subcutaneous administration, etc.), intracapsular administration, intravaginal administration, intraperitoneal administration, topical administration (powder, ointment, cream) , Sprays, lotions, etc.), buccal administration, nasal administration (sprays, drops, inhalants, etc.).

  An MTP inhibitor or complex can be administered alone, but generally selected from pharmaceutical excipients, adjuvants, diluents, and carriers known in the art according to the route of administration and pharmacy In the form of a mixture with one or more suitable drugs. Depending on the route of administration suitable for treatment and the release specificity, the MTP inhibitor or complex is formulated in the form of an immediate release formulation, delayed release formulation, modified release formulation, delayed release formulation, pulsed release formulation, or controlled release formulation. May be.

  The amount of MTP inhibitor or complex in the formulation may range from about 1% to about 75%, 80%, 85%, 90%, or even 95% (weight ratio). In the range of about 1%, 2%, or 3% to about 50%, 60%, or 70%, more typically in the range of about 1%, 2%, or 3% to less than 50% ( About 25%, 30%, 35%, etc.).

Methods for preparing various pharmaceutical preparations with specific amounts of active compounds are known to those skilled in the art (Remington, “The Practice of Pharmacy”
of Pharmacy ", Lippincott Williams
and Wilkins), Baltimore, Maryland, 20th edition, 2000, etc.).

  Examples of suitable formulations are described in WO03 / 002533, WO2005 / 046644, and WO2005 / 080373.

  For oral administration using liquid formulations, the liquid formulation may be a pharmaceutically acceptable emulsion, solution, suspension, syrup, elixir and the like. Liquid formulations may contain inert diluents common in the art in addition to the MTP inhibitor or complex. The inert diluent may be water, other solvents, solubilizers, emulsifiers, etc., such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol. , Dimethylformamide, oil (cotton seed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, etc.), Miglyol (trademark) (manufactured by Condea Vista Company, Cranford, NJ), glycerol, tetrahydrofurfuryl alcohol , Polyethylene glycol, sorbitan fatty acid ester, and mixtures thereof.

  The formulation may contain excipients such as wetting agents, emulsifiers, suspending agents, sweeteners, fragrances, and fragrances in addition to the inert diluent.

Oral liquid formulations of MTP inhibitors or conjugates contain a solution in which the active compound is completely dissolved. As the solvent, all solvents for oral administration which have precedents in the pharmaceutical field, in particular, those in which the compound of the present invention exhibits good solubility can be used. Examples of the solvent include polyethylene glycol, polypropylene glycol, edible oil, glyceryl-based and glyceride-based solvents. Glyceryl and glyceride solvents include Captex® 355EP (glyceryl tricaprylate / caprylate, manufactured by Abitec, Columbus, Ohio), Crodamol® GTC / C (medium Chain triglycerides, manufactured by Croda, UK, Cowick Hall, Labrafac® CC (medium chain triglide, manufactured by Gattefosse), Captex® 500P (glyceryl triacetate, That is, triacetin, manufactured by Abitec, Capmul (registered trademark) MCM (medium chain mono- and diglycerides, manufactured by Abitec), Migyol (registered trademark) 812 (capric / capric triglyceride, conde ( Condea), new Cranford, Jersey), Migyol (R) 829 (Capric / Capric / Succinic Triglyceride, Condea), Migyol (R) 840 (Propylene glycol dicaprylate / dicaprylate, Condea ( Condea), Labrafil® M1944CS (oleoyl macrogol-6 glyceride, manufactured by Gattefosse), Peceol® (glyceryl monooleate, manufactured by Gattefosse), mycin (Maisine, registered trademark) 35-1 (Glyceryl monooleate, manufactured by Gattefosse) and the like (for example, similar generic products). Of particular interest are medium chain (C ₈ -C ₁₀ ) triglyceride oils. The solvent is often the major component of the formulation, ie its content is greater than about 50%, usually greater than about 80% (eg about 95% or 99%). Adjuvants and additives may be added along with the solvent, and they are primarily used as deodorants, flavors, fragrances, antioxidants, stabilizers, texture modifiers, viscosity modifiers, and solubilizers.

  The suspension may contain a carrier such as a suspending agent in addition to the MTP inhibitor or the complexing agent. Examples of the suspending agent include ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth, and a mixture thereof.

  When administered to animals other than humans, an MTP inhibitor (or complex) can be included in the drinking water and a therapeutic dose of the compound can be conveniently consumed during daily watering. The compound can be directly measured in drinking water and is preferably used in the form of a liquid water-soluble concentrate (such as an aqueous solution of a water-soluble salt).

  Alternatively, the MTP inhibitor (or complex) itself or in the form of supplementary feed may be conveniently added directly to the food.

  The present invention has several advantageous veterinary properties. Owners and veterinarians who wish to lean animals and / or remove unwanted fat can achieve their desire using the method of the present invention. Poultry, cattle, and pig breeders can raise low-fat animals using the method of the present invention and provide more expensive products in the meat industry.

  Embodiments of the present invention will be described below with reference to examples. However, the embodiments of the present invention are not limited to the details of the examples, and those skilled in the art can conceive various improvements based on the disclosure of the present specification. Let's go.

Formulation: Composition per mL-Dilrotapide 5 mg, medium chain triglyceride oil 1 mL or less Feed: Gilpa Trinkets Completely Dried Food (Gilbertson) with a fat content of about 5%, 10%, or 15% of air-dried product・ And Page (Gilbertson
& Page), Wellin Garden City, UK) was given to dogs through the weight loss and retraining stages with a maintenance energy requirement of 1.2. At the end of the retraining phase prior to post-treatment, 90% of that was consumed in the final period of the feed consumption record.

The initial dose of dirlotapide was 0.1 mg / kg and a diet with different fat content was given for up to 52 weeks to treat overweight Labrador dogs, and the efficacy and safety of dirlotapide in this amount in Labrador dogs Investigated (further details are Gosserin (J. GOSSELLIN), Peach (S. PEACHY), Sherington (J. SHERINGTON), Rowan (TG ROWAN), Sunderland (S. J, SUNDERLAND), 2007, "Evaluation Of Dilrotapide for Sustained Weight Loss in Overweight Labrador Retrievers, Journal of Veterinary Pharmacology and Therapeutics (Journal
of Veterinary Pharmacology and Therapeutics), 30 (s1), 55-65, which is included in the disclosure by this reference). In this study, three consecutive treatments were performed. The weight loss phase was performed for a maximum of 168 days, and the dose was adjusted so that about 1 to 3% of body weight was lost in one week. The retraining phase lasted for a maximum of 196 days and the dosage was adjusted to maintain a body weight of ± 5% relative to the body weight at the end of the weight loss phase. Furthermore, the post-treatment stage was performed for a maximum of 31 days without giving a test substance.

  72 dogs were divided according to body condition score and body weight, randomly treated with 9 treatments, ie 168 days placebo (T1, T2, and T3, initial daily dose 0.02 mL / kg for the month of treatment initiation ), Up to 168 days of dirlotapide administration, followed by up to 196 days of placebo administration (T4, T5, and T6) and up to 364 days of dirlotapide administration (T7, T8, and T9). Prior to the start of treatment administration (Day 0), the dogs were accustomed to study residence, feed and environment for up to 39 days. Dogs were fed meals with varying fat content based on air dryness. That is, a meal with a fat content of 5% was given at T1, T4, and T7, a meal with a fat content of 10% at T2, T5, and T8, and a meal with a fat content of 15% at T3, T6, and T9. Dogs were weighed every 28 days throughout the weight loss, retraining, and post-treatment phases to assess physical condition, draw blood, assess fecal density, and conduct clinical tests. Furthermore, serum is collected from the dog on the 24th or 25th day of the weight loss stage, clinical observation is performed on the 0th to 14th days, and fecal density is evaluated on the 0th, 7th, 13th and 14th days. did. At T7, T8, and T9, dog body composition was evaluated on days -2 and 112 of the retraining phase and on day 28 of the post-treatment phase. On day 194 of the retraining phase, the remaining ophthalmologists were examined for vitamin deficiency-specific clinical signs in the dogs (T4-T9). In addition, subcutaneous adipose tissue was collected from dogs (T4 to T9) remaining on the last day of the retraining phase, and also on the last day of the study (T7 to T9). On the last day of the retraining phase, the vet examined all the remaining dogs (T4-T9) for vitamin deficiency specific clinical signs. Blood was analyzed for all biochemical aspects, and samples on the 24th / 25th day of the weight loss stage, the last day of the retraining stage, and the last day of the post-treatment stage were analyzed for clotting times of vitamin A, vitamin E, and prothrombin ( Prothrombin was not evaluated for samples at the weight loss stage 24/25).

  Dillotapide was administered for the treatment of overweight dogs for up to 52 weeks, and the drug was safe and effective. The weight of all dogs treated with dirlotapide was significantly reduced (P = 0.0001), and the mean weight loss per week for dogs treated with placebo was 0.02%, while the weight loss phase for dogs treated with dirlotapide was The average weight loss per week was 0.86%. Weight loss in dogs treated with dirlotapide continued during the retraining phase, albeit at a reduced rate, with an average weight loss of 0.2% per week in the retraining phase (the weight of placebo-treated dogs per week) An average of 0.65%).

  Compared to food intake during the acclimation period, the food intake at the weight loss stage for dogs treated with dirlotapide was significantly reduced (P = 0.0001). The average reduction in placebo-treated dogs was 17.1 vs 0.9%.

  During the weight loss and retraining phases, the average fat loss per week (weight basis) of dillrotapid treated dogs was 0.385 to 0.442%. On the other hand, the average change in lean body mass per week was -0.0196 to + 0.0021%, and it was confirmed that the lean body mass did not change much. None of the dogs treated with dirlotapid had an increased body condition score during the weight loss or retraining phase. On the other hand, the body condition score for dogs treated with placebo remained the same or higher.

  There were no serious side effects or suspicious phenomena during each period of the study.

Dosing The initial dose for placebo dogs is 0.02 mL / kg, which is equivalent to a dirlotapide dose of 0.1 mg / kg.

  Figures 1 and 2 show the effectiveness and safety of dirlotapide in the treatment of overweight in Labrador dogs (initial dose of dirlotapide is 0.1 mg / kg and a diet with different fat content is given for a maximum of 52 weeks). It is about research to show.

  In the dirlotapide-treated group, the dose increased during the weight loss phase (FIG. 1) and the final dose averaged 0.2-0.6 mg / kg. The final dose of the placebo-administered group (T1 to T3) averaged 0.19 to 0.20 mL / kg, reaching the maximum allowable dose. At the end of the weight loss phase, the dose was significantly higher in dogs fed a 5% fat diet compared to dogs fed a 15% fat diet (P = 0.0020, ie Further dose increase is required). Final doses at the weight loss stage averaged 0.50, 0.40, and 0.22 mg / kg body weight with fat content of 5%, 10%, and 15%, respectively.

During the weight loss phase, dogs treated with dirlotapide and dogs treated with placebo generally had significant therapeutic effects (P = 0.0001, Table 1) (average weight loss per week was 0.86% and 0, respectively). 0.02%). A significant interaction (P = 0.0066) was observed between the treatment and the feed, and a significant therapeutic effect was observed for each feed (P = 0.001 for the three fat-containing feeds).

  During the weight loss phase, the average cumulative weight loss of dogs treated with dirlotapide was consistent over time, ranging from 18.4 to 22.3% (three fat-containing diets, FIG. 2). In the case of dogs administered with placebo, the body weight remains almost constant (+ 1.5%) when using a diet with a fat content of 10% and a diet with 15%, and 4 for 168 days when using a diet with a fat content of 5%. A cumulative decrease of 2% was observed.

  Dogs treated with dirlotapide during the retraining phase and those treated with placebo after dirlotapide treatment in the weight loss phase generally showed significant therapeutic effects (P = 0.0001, Table 2) (average weight loss per week) Are 0.20% and 0.65% respectively). A significant interaction (P = 0.0004) was observed between the treatment and the feed, and a significant therapeutic effect was observed for each feed (P = 0.0001 for the three fat-containing feeds).

Feed intake Feed intake during the weight loss, retraining and post-treatment phases was compared to the adaptation period.

  During the weight loss phase, dogs treated with dirlotapid showed a significantly greater reduction in average daily feed intake (P = 0.0001) compared to dogs treated with placebo (Table 2, 17.1% and 0.001 respectively). 9%). There was no interaction between treatment and feed (P = 0.253).

  A summary of the weekly body weight change (%) during the weight loss phase is shown in Table 1, and a summary of the daily feed intake change (%) during the weight loss phase is shown in Table 2 as a percentage of the intake during the adaptation phase. 1 shows an outline of the dose and FIG. 2 shows an outline of the average cumulative body weight change (%) during the weight loss stage.

(4′-Trifluoromethyl-biphenyl-2-carboxylic acid [2- (2H- [1,2,4] triazol-3-ylmethyl) -1 to male Sprague-Dawley Rat], Effect of Subchronic Administration of 2,3,4-Tetrahydro-isoquinolin-6-yl] amide) Animals: Multiple male Sprague-Dawley rats (215-225 g, Charles River Laboratories, Delaware) Wilmington) were housed in suspended wire net cages at 21 ± 2 ° C., respectively, and the ambient light: dark cycle was 12 hours: 12 hours. These rats were given a refined powdered diet (D01060501M, D010060502M, Research Diets, New Brunswick, NJ) with a ratio of fat-derived calories to total calories of 10% or 45%, at approximately the same caloric density, arbitrarily Gave water. Prior to the experiment, all rats were habituated to the experimental diet and daily cycle for 8 days. All these procedures were conducted in accordance with the guidelines and regulations of the Institutional Animal Care and Use Committee.

  Study design: A total of 56 rats were used in this study. According to the randomization plan by www.randomization.com, 28 rats were randomly assigned to the low fat diet treatment group and the other 28 rats to the high fat diet treatment group. In order to minimize leakage, a metal lid and feed screen were attached to the glass food cup. Prior to compound administration, the 24-hour baseline food intake was measured for 4 days to confirm that the baseline food intake was not significantly different between treatment groups. Food intake measurement was continued until day 3 after compound administration. On the first day, and at about the same time on the first to third days, the body weight was measured. 0.5% methylcellulose excipient, or (4′-trifluoromethyl-biphenyl-2-carboxylic acid [2- (2H- [1,2,4] triazol-3-ylmethyl) -1,2, Rats were given a 0.5% methylcellulose suspension of 3,4-tetrahydro-isoquinolin-6-yl] amide). During three consecutive days, the dose was 0, 10, 30, or 100 mg / kg (10 mL / kg), the route of administration was normal oral administration, and the administration time was about 90 minutes before the dark cycle.

Changes in food intake and plasma endocrine mediators following administration of 10 mg / kg dirlotapide in rats fed a high-fat or low-fat diet Animal: Male Sprague-Dawley rats (initial body weight 125-135 g, Charles River Laboratories (Charles River Laboratories), Wilmington, Mass.) Were each housed in a suspended wire mesh cage at 21 ± 2 ° C. and the ambient light: dark cycle was 12 hours: 12 hours. These rats were given a refined powdered diet (low and high fat diets, D01060501M, D010060502M, Research Diets, New Brunswick, NJ) with 10% or 45% fat-derived calories as a percentage of total calories. They were given almost the same caloric density and optionally given water. To facilitate food intake measurements, metal lids and feed screens were attached to glass food bottles that were secured to the front of each cage with a metal spring or ring. Prior to the experiment, all rats were habituated to the diet and procedure for 5 days. All these procedures were conducted in accordance with the guidelines and regulations of the Institutional Animal Care and Use Committee.

  Design: A total of 40 male rats were used in this experiment. Twenty rats were randomly assigned to a group fed with a low fat diet and a group fed with a high fat diet, respectively. The 24-hour food intake was measured continuously for 3 days prior to compound administration (reference), and the food intake measurement was continued for 3 days after oral administration of the compound or vehicle to rats. During the treatment period, 10 rats in each feed group were further randomly given a group of polyethylene glycol 400 (PEG 400): saline = 80: 20 excipient, or 10 mg / kg to the excipient Assigned to the group giving the addition of dirlotapide. The dose was 1 mL per kg body weight. The administration route was normal oral administration, and the administration time was about 90 minutes before the dark cycle. Dillotapide or vehicle was administered for 4 consecutive days, food intake was measured for 24 hours on the first 3 days, and blood samples were taken on day 4 for analysis of compound effects and plasma endocrine mediators.

Blood collection: Approximately 16 hours after the fourth vehicle or dirlotapide administration, rats were killed by carbon dioxide inhalation and blood samples were collected by cardiac puncture. Blood was collected from tubes containing EDTA and aprotinin (0.6 TIU / mL, Phoenix Pharmaceuticals (Phoenix
Pharmaceuticals), Belmont, Calif.) To inhibit its enzymatic proteolysis. Plasma samples were stored frozen at approximately -20 ° C.

  Analysis of plasma peptide YY, cholescystokinin, urocortin, ghrelin, and intrapancreatic polypeptide: The total concentration of plasma peptide YY (PYY1-36 and PYY3-36) was determined by manufacturer's radioimmunoassay (RIA) using a commercial kit. Determined according to instructions for use (Phoenix Pharmaceuticals, Inc., Belmont, Calif. # RK-059-03). Plasma cholestyskinin (CCK), urocortin, and ghrelin concentrations were determined by enzyme-linked immunoassay (ELISA) using commercially available kits (Phoenix Pharmaceuticals, Belmont, Calif., #EK). -069-04, EK-019-15, EK-069-04). The concentration of intrapancreatic polypeptide (PP) was determined by the RIA method (Linco Research Inc., St. Charles, MO).

  Results: As a result of administration of 10 mg / kg dirlotapide for 3 consecutive days, when high-fat diet was given, daily food intake inhibition was a strong 43% on average, and weight gain compared to rats administered vehicle Decreased by 56% (FIG. 4). Compared to the vehicle-only standard, rats given a low-fat diet and treated with dirlotapide gave a small but significant reduction in food consumption (13%). Table 4 shows the changes in plasma concentrations of several known satiety factors following 4 days of vehicle or dirlotapide administration. Only rats fed a high fat diet were measured for humoral endocrine mediators in plasma. Plasma PYY concentrations in rats fed dirlotapide were significantly higher, 370% higher than in the vehicle.

  Dilrotapide was administered once a day to obese dogs who were veterinary patients, and the efficacy and safety of weight loss was assessed by a two-stage randomized study. In the first stage, placebo was used as a standard, and 28 obese dogs (body condition score (BCS) of 7 or more in a 9 stage evaluation) were used. Ten (6 males, 4 females) placebo dogs were given an initial dosage of 0.036 mL / lb of medium chain triglyceride (MCT) oil vehicle once a day (T1) and 18 ( Dilrotapid treated dogs (6 males and 12 females) were given an initial dose of 0.4 mg / kg (0.18 mg / lb) once daily (T2). On days 14 and 28, the dose was adjusted to 10% or 20%, and a 56% treatment resulted in a 1% to 3% reduction per week. In the second stage, 8 of the T2 treated dogs continue to be treated until 84 days (T2 extension), and 8 of the placebo dogs receive dirlotapide at an initial dose of 0.2 mg / kg (0.09 mg / lb). The dose was given for 84 days with monthly adjustment (T3). In the second stage, no reference animals were used. Body weight and BCS were recorded on day 0 and day 14, and thereafter monthly. For each treatment, the relationship between weight change (%) from day 0 and dietary fat (%) given to the dog was calculated.

  During the study, dogs were given a perfectly balanced commercial feed, but no dietary fat was specified in the protocol. Expressing the amount of dietary fat as a percentage of metabolic energy, T1 was 16% to 45%, T2 was 22% to 51%, and T3 was 16% to 45%. At T3, good between dietary fat and weight loss efficacy on day 28 (r = 0.8), day 56 (r = 0.8), and day 84 (r = 0.9) There was a relationship (if the fat content of the feed was high in kilocalorie%, the weight loss increased). At T2, many dogs lost more than 3% weekly on the 28th day (r = 0.1), but this effect was not seen, however, this effect was suggested on the 56th day (r = 0.4). It was done.

It is a figure which shows the outline | summary of the dosage during a research period. It is a figure which shows the outline | summary of the average cumulative body weight change (%) in the weight loss stage. A feed having a ratio of calories of fat to total calories of 45% (A) or 10% (B) is given, and (4'-trifluoromethyl-biphenyl-2-carboxylic acid [2- (2H- [1,2 , 4] triazol-3-ylmethyl) -1,2,3,4-tetrahydro-isoquinolin-6-yl] amide) (10, 30, or 100 mg / kg) or vehicle treated with vehicle It is a figure which shows the outline | summary of the average daily food intake. FIG. 6 is a diagram showing an overview of average daily food intake of rats treated with high fat or low fat diet and treated with dirlotapide (10 mg / kg) or vehicle.

Claims (10)

  A method of treating a subject exhibiting symptoms of obesity or related eating disorders and / or reduced food intake, characterized in that a therapeutically effective amount of an MTP inhibitor is given to the subject together with a high fat diet. Method.   Use of an MTP inhibitor in the manufacture of a medicament for treating a subject exhibiting symptoms of obesity or an associated eating disorder and / or reduced food intake, comprising a therapeutically effective amount of the MTP inhibitor together with a high fat diet Use characterized by giving to said subject.   3. The method or use according to claim 1 or 2, wherein the fat content of the high fat diet is about 10% or more based on the amount of air dried product.   4. The method or use according to claim 3, wherein the fat content of the high fat diet is about 15% or more based on the amount of air dried product.   The method or use according to claim 1 or 2, wherein a ratio of calories due to fat in the high fat diet to total calories of the high fat diet is about 24% or more.   6. The method or use according to claim 5, wherein the ratio of calories due to fat in the high fat diet to total calories of the high fat diet is about 34% or more.   Method or use according to any of the preceding claims, characterized in that the MTP inhibitor acts in the intestine. The MTP inhibitor is dirlotapide, mitratapide, (S) -2-[(4′-trifluoromethyl-biphenyl-2-carbonyl) -amino] -quinoline-6-carboxylic acid (pentylcarbamoyl). -Phenyl-methyl) -amide, (S) -2-[(4'-tert-butyl-biphenyl-2-carbonyl) -amino] -quinoline-6-carboxylic acid {[(4-fluoro-benzyl) -methyl -Carbamoyl] -phenyl-methyl} -amide, (S) -2-[(4′-tert-butyl-biphenyl-2-carbonyl) -amino] -quinoline-6-carboxylic acid [(4-fluoro-benzylcarbamoyl) ) -Phenyl-methyl] -amide, (S) -2-[(4′-isopropoxy-biphenyl-2-carbonyl) -amino]- Norin-6-carboxylic acid {[(4-fluoro - benzyl) - methyl - carbamoyl] - phenyl - methyl} - amide, the following formula:

Or (4′-trifluoromethyl-biphenyl-2-carboxylic acid [2- (2H- [1,2,4] triazol-3-ylmethyl) -1,2,3,4-tetrahydro -Isoquinolin-6-yl] amide), and pharmaceutically acceptable salts, hydrates, and solvates thereof, according to any of the preceding claims Method or use.   9. The method or use of claim 8, wherein the MTP inhibitor is dillrotapid.   The preceding claim, characterized in that after administering said MTP inhibitor, optionally a large amount of said MTP inhibitor is administered at least once, and optionally followed by weight maintenance / management or retraining. A method or use according to any of the above.

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