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WO1998019682A1 - Certains composes aminosterols et leur utilisation - Google Patents

Certains composes aminosterols et leur utilisation Download PDF

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Publication number
WO1998019682A1
WO1998019682A1 PCT/US1997/019595 US9719595W WO9819682A1 WO 1998019682 A1 WO1998019682 A1 WO 1998019682A1 US 9719595 W US9719595 W US 9719595W WO 9819682 A1 WO9819682 A1 WO 9819682A1
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WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
formula
efflux
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1997/019595
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English (en)
Inventor
Michael Zasloff
Jon Williams
William Kinney
Seth Alper
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Magainin Pharmaceuticals Inc
Original Assignee
Magainin Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Magainin Pharmaceuticals Inc filed Critical Magainin Pharmaceuticals Inc
Priority to AU51949/98A priority Critical patent/AU5194998A/en
Publication of WO1998019682A1 publication Critical patent/WO1998019682A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol

Definitions

  • Patent No. 5,192,756 to Zasloff, et al. which patent is entirely incorporated herein by reference.
  • This compound has the general molecular formula C 37 H 72 N 4 0 5 S and a calculated
  • compound 1436 and other aminosterols.
  • compound 1436 may be prepared from a
  • compound 1436 has been found to inhibit replication of the human
  • HIV immunodeficiency virus
  • SIV simian immunodeficiency virus
  • HSV herpes simplex virus
  • cancer has anti-proliferative effects that may assist in the treatment of various types of cancer.
  • the growth of various different types of cancer cells are inhibited by treatment with compound 1436, for example, the proliferation of human melanoma cells as well as murine acute lymphocytic leukemia (murine "ALL”) and human myeloid leukemic cells.
  • ALL murine acute lymphocytic leukemia
  • myeloid leukemic cells for example, the proliferation of human melanoma cells as well as murine acute lymphocytic leukemia (murine "ALL") and human myeloid leukemic cells.
  • compound 1436 In addition to treating various ailments and diseases, compound 1436 also may be used to reduce weight gain in mammals. The weight gain of the animals in these studies was controlled by appetite suppression and reduction in growth hormone production. The animals continued to have normal fluid consumption and were healthy, viable animals. Thus, compound 1436 may be used as a dietary aid to assist one in maintaining weight control in a healthy manner. Based on studies relating to weight gain, applicants have concluded that compound 1436 has metabolic effects and hormonal effects. These studies, as well as the diuretic effects of compound 1436, are described in U.S. Patent Appln. No. 08/857,288 mentioned above.
  • compound 1436 can selectively inhibit certain
  • NHEs sodium/proton exchangers
  • Several different isoforms of NHE are known to exist in mammals (e.g., NHEl, NHE2, NHE3, NHE4 and NHE5).
  • Compound 1436 has been found to specifically inhibit NHE3 and not NHEl or NHE2. Accordingly, compound 1436 may be used for treatment of proliferation or activation dependent conditions that rely on the function of NHE3, such as cancer, viral diseases, and ischemic reprofusion injury.
  • This invention relates to pharmaceutical compositions, including a compound according to formula 1436 as shown in Fig. la or the other aminosterols shown in Figs, lb-lg, or pharmaceutically acceptable salts thereof (as an active ingredient), and a pharmaceutically acceptable carrier or excipient.
  • the invention further relates to pharmaceutical products including the pharmaceutical composition described above.
  • Such pharmaceutical products may be provided for the treatment of gastric and duodenal ulcers; cardiac arrhythmia; cystic fibrosis; osteoporosis; constipation; post-menopausal dry mucosa syndrome; head trauma; Sj ⁇ gren's syndrome; or hypertension.
  • Gastric and duodenal ulcers could be treated by the inhibition of the CL channel which would reduce acid secretion in the stomach and duodenum.
  • Cystic fibrosis could be alleviated by activation of a Cl " channel to compensate for defective Cl " channels associated with the disease.
  • Osteoporosis can be treated by activation of Ca + " efflux in bone marrow cells.
  • Activation of Cl " efflux also produces water secretion, which can be useful for the treatment of Sj ⁇ gren's syndrome, constipation, and post-menopausal dry mucosa syndrome.
  • the inhibition of water secretion can be used to treat edema in head trauma.
  • Blockers of Ca ++ channels, such as compound 1521, could be used to treat cardiac arrhythmia and hypertension.
  • This invention further relates to various methods for using the pharmaceutical compositions in accordance with the invention.
  • various diseases or symptoms of diseases or ailments are treated by administering an effective amount of the above-described pharmaceutical compositions.
  • "Treat,” “treated,” or “treating,” as used in this application may mean complete elimination of the disease, ailment, or symptoms, or it may mean reducing, suppressing, or ameliorating the severity of the disease, ailment, or symptoms.
  • cardiac arrhythmia, hypertension, gastric ulcers, duodenal ulcers, Sjogren's syndrome, constipation, post-menopausal dry mucosa syndrome, head trauma, and cystic fibrosis may be treated by administering an effective amount of the pharmaceutical
  • compositions in accordance with the invention may be controlled (e.g., up regulated or inhibited) by administering an effective amount of the above- described pharmaceutical compositions.
  • the Ca 2+ -activated chloride efflux channel can be activated or inhibited, or AE-mediated anion exchange can be inhibited, by administering an effective amount of the pharmaceutical compositions in accordance with the invention.
  • Fig. 3 is a graph that illustrates that 1436 activates the chloride efflux channel; Figs. 4a and 4b illustrate that 1436 is inactive when injected into oocytes; Figs. 5a and 5b show the effect of calcium ions on the activity of compound 1436; Figs. 6a and 6b illustrate the effects of injected EGTA and BAPTA on the activity of compound 1436 ("EGTA” stands for ethylene glycol-bis( ⁇ -aminoethyl ether) N,N,N',N'- tetraacetic acid, and "BAPTA” stands for l,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid);
  • EGTA stands for ethylene glycol-bis( ⁇ -aminoethyl ether) N,N,N',N'- tetraacetic acid
  • BAPTA stands for l,2-bis(2-aminophenoxy)ethane-N
  • Fig. 7 is a graph showing that 1436 activates the 45 Ca-efflux channel;
  • Figs. 8a through l ib show the effect of compound 1436 on the Ca-effiux channel and the chloride efflux channel under a variety of conditions;
  • Fig. 12 shows the dose response of 1436 in the absence of calcium ions
  • Fig. 13 is a chart that shows the effect of various aminosterols on chloride efflux
  • Fig. 14 is a graph that illustrates the effect of compound 1521 on the activity of compound 1436 with respect to Cl " efflux;
  • Fig. 15 illustrates that in the presence of compound 1521, DIDS activates the chloride
  • Fig. 16 demonstrates the effect of guanine nucleotides on the activity of compound 1436
  • Fig. 17 shows AE1 and AE2 inhibition by various aminosterol compounds
  • Fig. 18 is a graph that illustrates inhibition of AE-mediated Cl " influx by compound 1361;
  • Fig. 19 is a graph illustrating AE2 inhibition as a function of compound 1360 dosage
  • Fig. 20 shows ID 50 values of aminosterols for 36 C17C1 ⁇ exchange
  • Figs. 21 through 28 show a schematic diagram for a voltage clamp device and various graphs illustrating the effect of compound 1436 on cells under various conditions
  • Figs. 29a and 29b demonstrate the change in oocyte pH after acid loading in the absence of compound 1436 and in the presence of compound 1436;
  • Fig. 30 shows the effect of compound 1436 on pH recovery in Xenopus oocytes.
  • Fig. 31 shows a pharmacokinetic study of 1436 in blood plasma after s.q. administration.
  • cells contain other pumps, carriers, channels, and the like that cells use to regulate various characteristics and functions of the cells. Tests were performed on compound 1436 to determine its effect on the Ca 2+ -activated chloride efflux channel. It was found that 1436 activates this efflux channel. The test results will be described below.
  • compound 1436 could not be evaluated as an anion exchange (AE) channel inhibitor because it activated an endogenous 36 C1 " efflux response in both water-injected and native Xenopus oocytes.
  • Figs. 2a and 2b demonstrate the effect of compound 1436 on 36 C1 " efflux and influx in
  • Figures 5a and 5b demonstrate that calcium ions (“[Ca ++ ] ! ”) improve the action of compound 1436.
  • the 1436 concentration is 2 ⁇ M in each instance.
  • compound 1436 activates endogenous Ca +T signaling in Xenopus oocytes. As shown in Fig. 7, compound 1436 activated the 45 Ca" " efflux channel when administered in a concentration of 2 ⁇ M. Additional graphs and charts are provided in Figs. 8a to 12 to show the effect of 1436 on the [Ca “1” "], and Cl " efflux pathways of oocytes under various conditions.
  • ND-96 is a balanced salt buffer solution for oocytes that contains (in mM): 96 NaCl, 2KC1, 1.8 MgCl 2 , 1 CaCl 2 , and 5 HEPES (Na), pH 7.40.
  • compound 1436 is active under both of these conditions.
  • Compound 1521 acts as an antagonist of the 1436-activated Cl " efflux. This effect is illustrated in Fig. 14. Notably, compound 1436 produces a high Cl' efflux when present alone at a concentration of 150 nM. When this concentration of compound 1436 is present together with
  • compound 1436 either (a) interacts with a surface receptor that elevates intracellular Ca ++ as part of its signaling mechanism, or (b) interacts directly with an exofacial domain of the Ca ++ regulated Cl " channel or an associated protein.
  • the aminosterols in Figs, la to lg have differing effects as antagonists of the heterologous AE-mediated anion exchange ( 36 C1 " efflux) in Xenopus oocytes.
  • the test results are illustrated in Fig. 17.
  • defolliculated oocytes were injected with cRNA encoding AE1 or AE2. Forty-eight or more hours later, the oocytes were acutely injected with Na 36 Cl, and efflux of the isotope was monitored into ND-96 in the absence or presence of the indicated aminosterols.
  • Each 36 C1 ' efflux experiment represents the indicated number of oocytes monitored, first in the absence of the aminosterol compound, and then after exposure to a 2 ⁇ M concentration of the noted aminosterol from Figs, la to lg (compound 1508, as shown in Fig. le, is a putative polya ine oxidase metabolite of 1436, and compound 1521 (Fig. If) can be characterized as a desulfated version of compound 1436).
  • the system was allowed to achieve a steady-state efflux rate.
  • Squalamine did not affect the mouse AE1 - or AE2-mediated 36 C1" fluxes of the Xenopus oocytes.
  • Compound 1437 hydroxymethylsqualamine
  • substantially inhibited AE2 activity by about 43%), and notably, it had little effect on the AE1 activity.
  • ND-96 included 2 ⁇ M 1361 aminosterol in some tests and no 1361 aminosterol in other tests.
  • the 36 C1 " influx was measured under the same extracellular conditions.
  • 1361 inhibited AE1 by 46% and AE2 by 53% (in the graph of Fig. 18, the " * " indicates that p ⁇ 0.05).
  • This essentially equivalent inhibition of AE1 and AE2 at long exposure times differs from the 8-10 fold greater potency displayed for AE2 inhibition when measured at short exposure times, as shown in Fig. 17.
  • Fig. 19 is a graph that illustrates the 1360 dose response for inhibiting the AE2-mediated 36 C1 " efflux channel in oocytes.
  • .Oocytes were injected with cRNA encoding mouse AE2. Forty- eight hours later, the oocytes were acutely injected with Na 36 Cl. 36 C1 efflux was monitored, first in the absence of compound 1360, and then in the presence of the indicated increasing concentrations of compound 1360.
  • Efflux rate constants were calculated by linear regression of the efflux curves, and percent inhibition was calculated as follows:
  • %Inh. 100 x [1 - (rate constant with 1360 present / rate constant with 1360 absent)]. Notably, even at relatively low 1360 dosages (about 500 nM), about 50% or more Cl " efflux inhibition was observed. Applicants conclude from this data that 1360 inhibits AE2 in a manner consistent with interaction at a single site.
  • Xenopus oocytes Values for both AE1 and AE2 anion exchange were measured. See Fig. 20.
  • Each 36 C1" efflux experiment noted in Fig. 20 represents one oocyte monitored, first in the absence of any aminosterol, and then after exposure to the noted aminosterol compound in at least three graded concentrations. Each successive concentration was maintained until achievei ⁇ ent of a new, steady-state efflux rate. This steady-state condition always was reached within about 16 minutes. All of the experiments described in conjunction with Fig. 20 included a final exposure to DIDS, at a concentration of 200 ⁇ M, to confirm the integrity of the carrier- mediated Cl" transport. These ID 50 values were derived from a non-linear fit to a hyperbolic inhibition curve.
  • FIG. 21 A schematic diagram of a voltage-clamp recording apparatus is illustrated in Fig. 21. Current, conductance and potential measurements were made on cell systems in the presence of compound 1436, under various experimental conditions, as shown in Figs. 22-28.
  • Oocyte pH regulates AE2 activity
  • oocyte NHE regulates pH
  • Figs. 29a and 29b illustrate pHj traces of oocyte pairs that are allowed to recover from NH 4 CI- induced acid loading in the absence (Fig. 29a) and in the presence (Fig. 29b) of the aminosterol 1436.
  • the oocytes were preloaded with a pH sensitive radiometric dye acetoxymethyl ester, BCECF-AM. Loaded oocytes were acidified by incubation in 20mM NH 4 C1, and then allowed to recover.
  • Fig. 29a when compound 1436 is not present, pH recovery is relatively rapid.
  • the pH remains low. Additional pH j data is included in Fig. 30. From this data, applicants conclude that compound 1436 inhibits oocyte Na/H exchange that is activated by acid loading.
  • Squalamine has been found to be an inhibitor of mammalian NHE3-mediated Na/H exchange. As shown above, applicants have examined the activity of aminosterols on cation exchange and anion exchange in Xenopus oocytes. The endogenous Na/H exchanger of
  • Xenopus oocytes mediates -60% of recovery from an ammonium chloride-induced acid load, as defined by blockade of pH f recovery by extracellular Na + removal or by 100 ⁇ M amiloride.
  • Compound 1521 is an antagonist of 1436-activated Cl" efflux
  • Blockers of the nonerythroid AE channels such as the aminosterols 1360 and 1361 have many potential uses. For example, they may be used in the treatment of gastric and duodenal ulcers by inhibition of gastric lumenal acid secretion. Activation of the calcium activated chloride channel, as demonstrated by 1436, may be useful, for example, in the treatment of Sj ⁇ gren's syndrome or cardiac arrhythmia.
  • the mode of administration of compound 1436 and the other aminosterol compounds may be selected to suit the particular therapeutic use. Modes of administration generally include, but are not limited to, transdermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, inhalation, intralesional, endothelial and oral routes.
  • the compounds may be administered by any convenient route, for example, by infusion or bolus injection, or by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and the active aminosterol ingredient may be administered together with other biologically active agents. Administration may be local or systemic.
  • the abbreviation “s.q.” or “s.c.” is used to represent subcutaneous administration of compound 1436 or other substances.
  • the abbreviation “i.p.” is used to represent intraperitoneal administration of compound 1436 or other substances.
  • the abbreviation “i.v.” is used to represent intravenous administration of compound 1436 or other substances.
  • the abbreviation “i.m.” is used to represent intramuscular administration of compound 1436 or other substances.
  • the present invention also provides pharmaceutical compositions that include compound 1436 or another aminosterol compound as an active ingredient.
  • Such pharmaceutical compositions include a therapeutically effective amount of compound 1436 (or a pharmaceutically acceptable salt thereof) or another aminosterol compound (or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier or excipient.
  • Such a carrier examples include, but are not limited to, saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof.
  • saline buffered saline
  • dextrose dextrose
  • water glycerol
  • ethanol ethanol
  • combinations thereof The particular form and formulation of the pharmaceutical composition should be selected to suit the mode of administration.
  • the pharmaceutical composition if desired, also may contain minor amounts of wetting
  • the pharmaceutical composition may be in any suitable form, such as a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder.
  • the pharmaceutical composition also may be formulated as a suppository, with traditional binders and carriers, such as triglycerides.
  • Oral formulations may include standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
  • Various delivery systems are known and may be used to administer a therapeutic compound of the invention, e.g., encapsulation in liposomes, microparticles, microcapsules and the like.
  • the pharmaceutical composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to humans.
  • compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • the pharmaceutical composition also may include a
  • solubilizing agent and a local anesthetic to ameliorate pain at the cite of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water-free concentrate in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent.
  • a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent.
  • the pharmaceutical composition may be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline may be provided so that the ingredients may be mixed prior to administration.
  • the amount of the therapeutic compound of the invention that will be effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and this amount can be determined by standard clinical techniques known to those skilled in the art through routine experimentation.
  • the precise dose to be employed in the pharmaceutical composition also will depend on the route of administration and the seriousness of the disease or disorder, and should be decided according to the judgement of the practitioner and each patient's circumstances. Effective therapeutical doses may be determined from extrapolations of dose-response curves derived from in vitro or animal-model test systems.
  • the following dosage ranges are exemplary. Suitable dosages for intravenous administration are generally about 20 micrograms to 40 milligrams of active compound per kilogram body weight. Suitable dosage ranges for intranasal administration are generally about 0.01 mg/kg body weight to 1 mg/kg body weight. Suitable dosage ranges for topical administration are generally at least about 0.01% by weight. Suitable dosages for oral
  • administration are generally about 500 micrograms to 800 milligrams per kilogram body weight
  • Suppositories generally contain, as the active ingredient, 0.5 to 10% by weight of the aminosterol active ingredient.
  • Oral formulations are particularly preferred.
  • Exemplary dosages of the aminosterol active ingredient for most pharmacological or therapeutical uses fall within the range of about 0.01 mg/kg body weight to about 100 mg/kg body weight. Preferred dosages are from 0.1 to 25 mg/kg body weight.
  • Fig. 31 shows the blood plasma levels of compound 1436 at various times after this s.q. administration.
  • the peak 1436 concentration in the blood plasma from this 10 mg/kg dose was about 175 ⁇ g/ml after a time of about 2 hours. After 48 hours, the 1436 concentration is still about 10-15 ⁇ g/ml.
  • This data indicates that relatively small 1436 doses may be used for s.q. administration. This data also provides an indication that oral dosing of 1436 will be effective.
  • the invention also may include a pharmaceutical pack or kit including one or more containers filled with pharmaceutical compositions in accordance with the invention.
  • Associated with such containers may be a notice in the form prescribed by a government agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de régulation (par exemple, inhibition, activation ou régulation positive) de canaux variés d'ions de cellules comportant le contact de la cellule avec une quantité efficace d'un composé aminostérol ou d'un sel de celui-ci. Ce contact peut être réalisé, par exemple, en administrant une composition pharmaceutique à un patient, laquelle composition comporte un vecteur pharmaceutique acceptable ou un excipient et au moins un composé aminostérol. Le procédé de l'invention peut être utilisé de façon à traiter des ulcères (par exemple, ulcères gastriques ou duodénaux), l'arythmie cardiaque, le syndrome de Sjögren, la mucoviscidose, un traumatisme crânien, la constipation, le syndrome des muqueuses sèches post-ménauposique, l'ostéoporose ou l'hypertension.
PCT/US1997/019595 1996-11-01 1997-10-31 Certains composes aminosterols et leur utilisation Ceased WO1998019682A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU51949/98A AU5194998A (en) 1996-11-01 1997-10-31 Certain aminosterol compounds and uses therefor

Applications Claiming Priority (2)

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US2954196P 1996-11-01 1996-11-01
US60/029,541 1996-11-01

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WO1998019682A1 true WO1998019682A1 (fr) 1998-05-14

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999065462A3 (fr) * 1998-06-19 2000-04-13 Genzyme Corp Transport du chlore par petites molecules
WO2002006299A3 (fr) * 2000-07-13 2002-06-06 Genaera Corp Utilisations therapeutiques de composes d'aminosterols
US6706732B1 (en) 1999-06-03 2004-03-16 Takeda Chemical Industries, Ltd. Nasal preparation of guanidinoimino quinoline derivatives
US7786119B2 (en) 2004-04-01 2010-08-31 Cardiome Pharma Corp. Drug conjugates of ion channel modulating compounds
CN106535902A (zh) * 2014-06-23 2017-03-22 M·札斯洛夫 用于刺激肠内分泌系统以治疗与其相关的疾病或状况的方法和组合物

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WO1995024415A1 (fr) * 1994-03-10 1995-09-14 Magainin Pharmaceuticals Inc. Derives de steroides, compositions pharmaceutiques les contenant et leur utilisations pharmaceutiques
WO1996040151A1 (fr) * 1995-06-07 1996-12-19 Magainin Pharmaceuticals Inc. Utilisation de squalamine dans la production d'un medicament inhibant le nhe
WO1996040728A2 (fr) * 1995-06-07 1996-12-19 Magainin Pharmaceuticals Inc. Composes d'aminosterol utiles comme inhibiteurs de l'echangeur sodium/proton (nhe), methodes et compositions pharmaceutiques utilisant ces inhibiteurs, et procedes d'evaluation de l'efficacite inhibitrice du nhe desdits composes
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Publication number Priority date Publication date Assignee Title
WO1995024415A1 (fr) * 1994-03-10 1995-09-14 Magainin Pharmaceuticals Inc. Derives de steroides, compositions pharmaceutiques les contenant et leur utilisations pharmaceutiques
WO1996040151A1 (fr) * 1995-06-07 1996-12-19 Magainin Pharmaceuticals Inc. Utilisation de squalamine dans la production d'un medicament inhibant le nhe
WO1996040728A2 (fr) * 1995-06-07 1996-12-19 Magainin Pharmaceuticals Inc. Composes d'aminosterol utiles comme inhibiteurs de l'echangeur sodium/proton (nhe), methodes et compositions pharmaceutiques utilisant ces inhibiteurs, et procedes d'evaluation de l'efficacite inhibitrice du nhe desdits composes
WO1997044044A1 (fr) * 1996-05-17 1997-11-27 Magainin Pharmaceuticals Inc. Utilisations therapeutiques d'un compose d'aminosterol

Non-Patent Citations (5)

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Title
S.L. ALPER: "Shark aminosterols inhibit murine AE2 and AE1 and the endogenous Na/H exchanger in Xenopus oocytes", J. AM. SOC. NEPHROL., vol. 7, no. 9, September 1996 (1996-09-01), pages 1249, XP002059790 *
US 08/474,799 (1995) *
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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999065462A3 (fr) * 1998-06-19 2000-04-13 Genzyme Corp Transport du chlore par petites molecules
US6323191B1 (en) 1998-06-19 2001-11-27 Genzyme Corporation Small molecule chloride transport
US6706732B1 (en) 1999-06-03 2004-03-16 Takeda Chemical Industries, Ltd. Nasal preparation of guanidinoimino quinoline derivatives
WO2002006299A3 (fr) * 2000-07-13 2002-06-06 Genaera Corp Utilisations therapeutiques de composes d'aminosterols
US7410959B1 (en) 2000-07-13 2008-08-12 Genaera Corporation Therapeutic uses for aminosterol compounds
US8987236B2 (en) 2000-07-13 2015-03-24 Ohr Pharmaceutical, Inc. Therapeutic uses for an aminosterol compound
US7786119B2 (en) 2004-04-01 2010-08-31 Cardiome Pharma Corp. Drug conjugates of ion channel modulating compounds
US20180002370A1 (en) * 2013-10-03 2018-01-04 Enterin Laboratories, Inc. Methods of treating and/or preventing affective disorders of the nervous system (depression) using aminosterols
US10040817B2 (en) 2013-10-03 2018-08-07 Enterin Laboratories, Inc. Methods and compositions for stimulation of the intestinal enteroendocrine system for treating diseases or conditions related to the same
US10196420B2 (en) 2013-10-03 2019-02-05 Enterin Laboratories, Inc. Methods of treating and preventing gastrointestinal motility disorders using aminosterols
US10208079B2 (en) 2013-10-03 2019-02-19 Enterin Laboratories, Inc. Methods of treating and/or preventing neurodevelopmental disorders (autism) using aminosterols
US10208080B2 (en) 2013-10-03 2019-02-19 Enterin Laboratories, Inc. Methods of treating and/or preventing affective disorders of the nervous system (depression) using aminosterols
US10633413B2 (en) 2013-10-03 2020-04-28 Enterin, Inc. Methods of treating Parkinson's disease using aminosterols and compositions comprising the same
US10975116B2 (en) 2013-10-03 2021-04-13 Enterin, Inc. Methods of treating and preventing gastrointestinal motility disorders using aminosterols
US11440936B2 (en) 2013-10-03 2022-09-13 Enterin, Inc. Methods and compositions for stimulation of the intestinal enteroendocrine system for treating diseases or conditions related to the same
CN106535902A (zh) * 2014-06-23 2017-03-22 M·札斯洛夫 用于刺激肠内分泌系统以治疗与其相关的疾病或状况的方法和组合物
EP3157531A4 (fr) * 2014-06-23 2018-05-16 Michael Zasloff Procédés et compositions pour la stimulation du système entéro-endocrinien intestinal pour le traitement de maladies ou d'états pathologiques associées à celui-ci

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