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WO2017083242A1 - Inhibiteurs de la suppression de la tumorigénicité 2 (st2) et leurs procédés d'utilisation - Google Patents

Inhibiteurs de la suppression de la tumorigénicité 2 (st2) et leurs procédés d'utilisation Download PDF

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WO2017083242A1
WO2017083242A1 PCT/US2016/060890 US2016060890W WO2017083242A1 WO 2017083242 A1 WO2017083242 A1 WO 2017083242A1 US 2016060890 W US2016060890 W US 2016060890W WO 2017083242 A1 WO2017083242 A1 WO 2017083242A1
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substituted
alkyl
heterocycloalkyl
heteroaryl
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Chao-Yie Yang
Sophie PACZESNY
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Indiana University Research and Technology Corp
University of Michigan System
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University of Michigan System
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to inhibitors of Suppression of Tumorigenicity 2 (ST2) and to therapeutic methods of treating conditions and diseases wherein inhibition of ST2 provides a benefit.
  • ST2 Tumorigenicity 2
  • ST2 also known as IL1RL1, DER4 ,and Tl, is a binding receptor for interleukin-33 (IL-33), a cytokine related to IL-1 and IL-18.
  • ST2 is expressed both as a soluble non- signaling variant (soluble ST2 or sST2) and a full-length membrane- spanning form (FL ST2, ST2 or ST2L) that mediates cellular responses to IL-33.
  • soluble ST2 or sST2 soluble non- signaling variant
  • FL ST2, ST2 or ST2L full-length membrane- spanning form
  • lymphocytes particularly IL-5 and IL-13 -expressing T helper cells, natural killer (NK), and natural killer-T (NKT) cells, as well as many innate immune cells, such as mast cells, basophils, eosinophils, macrophages, and innate helper cells (also known as nuocytes).
  • NK natural killer
  • NKT natural killer-T
  • innate immune cells such as mast cells, basophils, eosinophils, macrophages, and innate helper cells (also known as nuocytes).
  • ST2L or membrane ST2 is the full-length protein and includes the extracellular immunoglobulin (Ig)-like domains, a short extracellular spacer, the transmembrane domain, and an intracellular TIR domain.
  • Soluble ST2 (sST2) is a short form that lacks the final three exons, resulting in a soluble secreted protein consisting of the extracellular cytokine-binding domains.
  • sST2 is present constitutively in human serum/plasma, where it acts as a decoy receptor by binding free IL-33.
  • sST2 is increased by diverse inflammatory stimuli and in cardiovascular, rheumatologic, allergic diseases, and graft-versus-host disease (GVHD) potentially restricting the effects of systemic IL-33 (either deleterious or positive.
  • GVHD graft-versus-host disease
  • GWASs genome-wide association studies
  • IL1RL1 variants associated with altered levels of serum sST2, which could influence susceptibility to IL-33-mediated responses.
  • IL-33 binding to ST2 on these cells leads to the recruitment of a broadly-expressed co-receptor known as the IL-1R Accessory Protein (AcP) and the activation of proinflammatory signaling, similar to IL-1 and IL-18.
  • IL-33 thus is able to directly activate ST2- expressing cells or enhance their activation when in the presence of other activating stimuli.
  • Examples of IL-33-induced cellular responses include the production of inflammatory cytokines, such as IL-5, IL-6, IL-13, TNF, IFN-g, and GM-CSF, as well as the production of chemokines, such as CXCL8, CCL17, and CCL24.
  • IL-33 has also been shown to enhance acute allergic responses by augmenting mast cell and basophil activation triggered by IgE receptor signaling or other mast cell and basophil activators. IL-33 also enhances recruitment, survival, and adhesive properties of ST2 expressing immune cells, and thus is important in provoking and sustaining cellular inflammation in local tissues.
  • IL-33 The pro-inflammatory actions of IL-33 on innate and adaptive immune cells culminate to promote a number of pathologic processes. In the lungs, these include increased airway inflammation, mucus production, airway hyper responsiveness, and fibrotic remodeling. IL-33 can also contribute to localized inflammation in the joints, as well as cutaneous and articular hypernociception, by promoting the production of proinflammatory cytokines. Excessive IL-33 has been linked to pathologic collagen deposition and fibrosis and also contributes to epithelial damage in the setting of inflammatory bowel disease.
  • IL-33 Through its potent effects on basophils and IgE-sensitized mast cells, IL-33 also can trigger anaphylactic shock and may play a contributing role in allergic disease. Many of these diseases are chronic and progressive in nature and are difficult to treat.
  • IL-33/ST2 pathway contributes to human disease.
  • abnormally high expression of IL-33 is found in diseases involving inflammation in mucosal tissues and articular inflammation. These include asthma, inflammatory bowel disease, and rheumatoid arthritis.
  • IL-33 expression is elevated in psoriatic skin and the skin of atopic dermatitis patients and also is increased in pathologic settings of fibrosis, such as systemic sclerosis and liver fibrosis.
  • Examples include asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, sepsis and trauma, HIV infection, systemic lupus erythematosus, inflammatory bowel disease, rheumatoid arthritis, sclerosis, Wegener's granulomatosis, Behcet's disease, and cardiovascular disease.
  • IL-33 potentiates eosinophillic inflammation, and evidence exists that this pathway is involved in eosinophil-associated disease, such as rhinosinusitis, nasal polyposis, and eosinophilic bronchitis.
  • HSCT hematopoietic stem cell transplantation
  • GVHD graft-versus-host disease
  • sST2 acts as a decoy receptor for IL-33, the only known ligand for ST2, which drives Th2 cells toward a Thl phenotype.
  • the present invention is directed to small molecule inhibitors of ST2, to compositions comprising the inhibitors, and to methods of using the inhibitors in a therapeutic treatment of conditions and diseases wherein inhibition of ST2 activity provides a benefit.
  • the soluble form of ST2 is the most significant biomarker to predict a failure to respond to GVHD therapy. Therefore, one aspect of the invention is to identify small molecule compounds that target ST2 and that can be used to alleviate GVHD.
  • Another aspect of the present invention is to identify small molecule compounds that inhibit ST2, and therefore are useful in the treatment of hematological cancers by alleviating GVHD associated with cancer treatments.
  • Yet another aspect to the present invention is to provide a method of treating other diseases and conditions mediated by ST2, both the soluble form of ST2 and the full length form, by administering a therapeutically effective amount of a small molecule compound capable of inhibiting the ST2-IL33 interaction in an individual in need thereof.
  • diseases and conditions are GVHD, cardiovascular diseases, asthma, lupus, and other Thl/Th2 imbalanced inflammatory diseases.
  • Another aspect of the present invention is to identify small molecules capable of inhibiting ST2. Still another aspect of the invention is to utilize these compounds, or a composition containing one or more of these compounds, in the treatment of a disease or condition by the administration of a therapeutically effective amount of one or more of these compounds to an individual in need thereof.
  • a class of compounds capable of inhibiting ST2 has a structural formula (I)
  • R 1 is selected from the group consisting of R b , -Ci_ 3 alkyl , substituted or unsubstituted heteroaryl, substituted and unsubstituted aryl,
  • R is selected from the group consisting of
  • R a is H, substituted or unsubstituted aryl, or Ci_ 4 alkyl;
  • R b is H, substituted or unsubstituted aryl, optionally
  • R c is Ci_ 3 alkyl, -(CH 2 )i_ 3 OCi_ 3 alkyl, -(CH 2 )i_ 3 C0 2 H, substituted or unsubstituted
  • R d is substituted or unsubstituted aryl, -(CH 2 )i_ 3 OCi_ 4 alkyl, -(CH 2 )i_ 3 heteroaryl, and -(CH 2 )i_ 3 heterocycloalkyl;
  • n O or l
  • a second class of compounds capable of inhibiting ST2 has a structural formula (II):
  • R° is -N0 2 , halo, or -CN
  • R e is H or -Ci_ 4 alkyl
  • a third class of compounds capable of inhibiting ST2 has a structural formula (III):
  • Z is null, NR 5 or S
  • D is -CH 2 - or /
  • R 4 is phenyl, heteroaryl, -(CH 2 )i_ 2 heteroaryl, cycloalkyl,
  • heterocycloalkyl -C 6 H 5 -0-R h , -(CH 2 )i_ 2 -C 6 H 5, or -(CH 2 )i_ 3 OR h ;
  • R 5 is null, H, or -(CH 2 )i_ 3 OR h , or
  • R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a heteroaryl group or a substituted or unsubstituted heterocycloalkyl group;
  • R f is Ci_ 3 alkyl or ; [0043] R g is H or halo; and [0044] R h is H or Ci_ 3 alkyl, or [0045] a pharmaceutically acceptable salt thereof.
  • Additional compounds capable of inhibiting ST2 include the following compounds of embodiment (IV):
  • a p armaceut ca y accepta e sa t t ereo .
  • Another embodiment of the present invention is to provide a composition
  • a composition comprising (a) an ST2 inhibitor of embodiments (I)-(IV) and (b) an excipient and/or pharmaceutically acceptable carrier useful in treating diseases or conditions wherein inhibition of ST2 provides a benefit.
  • Another embodiment of the present invention is to utilize a composition comprising a compound of embodiments (I)-(IV) and a second therapeutically active agent in a method of treating an individual for a disease or condition wherein inhibition of ST2 provides a benefit.
  • the invention provides for use of a composition comprising an ST2 inhibitor of embodiments (I)-(IV) and an optional second therapeutic agent for the manufacture of a medicament for treating a disease or condition of interest, e.g., asthma or lupus.
  • a disease or condition of interest e.g., asthma or lupus.
  • Still another embodiment of the present invention is to provide a kit for human pharmaceutical use comprising (a) a container, (bl) a packaged composition comprising an ST2 inhibitor of embodiments (I)-(IV), and, optionally, (b2) a packaged composition comprising a second therapeutic agent useful in the treatment of a disease or condition of interest, and (c) a package insert containing directions for use of the composition or compositions, administered simultaneously or sequentially, in the treatment of the disease or condition.
  • An ST2 inhibitor of embodiments (I)-(IV) and the second therapeutic agent can be administered together as a single-unit dose or separately as multi-unit doses, wherein the ST2 inhibitor of embodiments (I)-(IV) is administered before the second therapeutic agent or vice versa. It is envisioned that one or more dose of an ST2 inhibitor of embodiments (I)-(IV) and/or one or more dose of a second therapeutic agent can be administered.
  • an ST2 inhibitor of embodiments (I)-(IV) and a second therapeutic agent are administered simultaneously.
  • an ST2 inhibitor of embodiments (I)-(IV) and a second therapeutic agent are administered from a single composition or from separate compositions.
  • the ST2 inhibitor of embodiments (I)-(IV) and second therapeutic agent are administered sequentially.
  • An ST2 inhibitor of embodiments (I)-(IV), as used in the present invention can be administered in an amount of about 0.005 to about 500 milligrams per dose, about 0.05 to about 250 milligrams per dose, or about 0.5 to about 100 milligrams per dose.
  • FIG 1 contains plots showing CD4 and CD8 T cell proliferation measured by CFSE dilution and IFN- ⁇ production measured by intracellular staining in mixed leukocyte reactions with DMSO or an ST2 inhibitor;
  • FIG 2 contains plots showing preservation of Treg cells in human mixed lymphocyte reactor with DMSO or an ST2 inhibitor;
  • FIG 3 contains plots for GVHD score and survival for NSG mice transplanted with human T cells after 300 cGy total body irradiation on day-1 and treated with DMSO or ST2 inhibitors administered via intra-peritoneal injection daily from day -1 to day 20 after HCT;
  • FIG 4 contains plots showing the percentage population of human IFNg+ and IL- 17+ CD4+ T cells and human Foxp3+ CD4+ Treg cells in live human CD45+CD4+ T cells collected from the gut after DMSO and ST2 inhibitors treatment at day 14 in the NSG mice;
  • FIG 5 contains plots showing the percentage population of human IFNg+ CD4+ T cells and human Foxp3+ CD4+ Treg cells in live human CD45+CD4+ T cells collected from the gut after DMSO and ST2 inhibitor treatment at day 21 in the NSG mice.
  • FIG 6 contains plots showing systemic human plasma ST2 and IFN- ⁇ in a DMSO or ST2 inhibitor treated groups at day 7, 14, 21 and day 28 after HCT;
  • FIG 7 contains plots showing GVHD score and survival for C3H.SW mice transplanted with B57B/6 bone marrow and T cells after 1100 cGy total body irradiation on day 1 with DMSO or an ST2 inhibitor administered via intra-peritoneal injection daily from day -1 to day 20 after HCT.
  • FIGS 8-13 contain plots of an ex vivo analysis of the C3H.SW mice CD4+T cells from the gut at Day 14 and 21 after HCT;
  • FIG 14 contains bar graphs summarizing the percentage (expressed in mean + standard error of the mean) population of mouse IFN-yt, T-bet+, RORgt+ T cells and Foxp3+ CD4+ Treg cells in CD4+ T cells collected from the gut after DMSO and ST2 inhibitor treatment at day 14 and on day 21 in the C3H.SW mice and
  • FIG 15 contains bar graphs showing systemic mouse plasma (expressed in mean + standard error of the mean) ST2 and IFN- ⁇ in a DMSO or ST2 inhibitor treated group at day 7 and 14 after HCT.
  • a disease or condition wherein inhibition of ST2 provides a benefit pertains to a condition in which ST2, either the soluble form or the full length form, is important or necessary, e.g., for the onset, progress, expression of that disease or condition, or a disease or a condition which is known to be treated by an inhibition of ST2.
  • Examples of such conditions include, but are not limited to, GVHD, cardiovascular disease, asthma, lupus, and other Thl/Th2 imbalanced inflammatory diseases.
  • ST2 Thl/Th2 imbalanced inflammatory diseases.
  • One of ordinary skill in the art is readily able to determine whether a compound treats a disease or condition mediated by ST2, for example, by assays which conveniently can be used to assess the activity of particular compounds.
  • second therapeutic agent refers to a therapeutic agent different from an ST2 inhibitor of embodiments (I)-(IV) and that is known to treat the disease or condition of interest.
  • the second therapeutic agent can be a known chemotherapeutic drug or radiation, for example.
  • Second therapeutic agents useful to treat an autoimmune disease, like lupus, are disclosed in WO 2008/144610, designating the U.S., and incorporated herein by reference.
  • disease or “condition” denotes disturbances and/or anomalies that as a rule are regarded as being pathological conditions or functions, and that can manifest themselves in the form of particular signs, symptoms, and/or malfunctions.
  • a compound of embodiments (I)-(IV) is a potent inhibitor of ST2 and can be used in treating diseases and conditions wherein inhibition of ST2 provides a benefit.
  • further conditions and diseases modified by IL- 33/SC-2 binding are disclosed in WO 2008/144610, designating the U.S. and incorporated herein by reference, specifically pages 51 and 52.
  • treat refers to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated.
  • the terms “treat,” “treating,” “treatment,” and the like may include “prophylactic treatment,” which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition, as is the case with GVHD.
  • proliferative treatment refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition, as is the case with GVHD.
  • the term “treat” and synonyms contemplate administering a therapeutically effective amount of a compound of the invention to an individual in need of such treatment.
  • treatment also includes relapse prophylaxis or phase prophylaxis, as well as the treatment of acute or chronic signs, symptoms and/or malfunctions.
  • the treatment can be orientated symptomatically, for example, to suppress symptoms. It can be effected over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy.
  • terapéuticaally effective amount refers to an amount of the active ingredient(s) that is(are) sufficient, when administered by a method of the invention, to efficaciously deliver the active ingredient(s) for the treatment of condition or disease of interest to an individual in need thereof.
  • the term "container” means any receptacle and closure therefor suitable for storing, shipping, dispensing, and/or handling a pharmaceutical product.
  • the term "insert” means information accompanying a pharmaceutical product that provides a description of how to administer the product, along with the safety and efficacy data required to allow the physician, pharmacist, and patient to make an informed decision regarding use of the product.
  • the package insert generally is regarded as the "label" for a pharmaceutical product.
  • Concurrent administration means that two or more agents are administered concurrently to the subject being treated.
  • concurrently it is meant that each agent is administered either simultaneously or sequentially in any order at different points in time. However, if not administered simultaneously, it is meant that they are administered to an individual in a sequence and sufficiently close in time so as to provide the desired therapeutic effect and can act in concert.
  • an ST2 inhibitor of embodiments (I)-(IV) can be administered at the same time or sequentially in any order at different points in time as a second therapeutic agent.
  • a present ST2 inhibitor and the second therapeutic agent can be administered separately, in any appropriate form and by any suitable route.
  • a present ST2 inhibitor and the second therapeutic agent can be administered in any order to a subject in need thereof.
  • a present ST2 inhibitor can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapeutic agent treatment modality (e.g., chemotherapy), to an individual in need thereof.
  • a second therapeutic agent treatment modality e.g., chemotherapy
  • an ST2 inhibitor of embodiments (I)-(IV) and the second therapeutic agent are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, no more than 24 hours apart or no more than 48 hours apart.
  • the components of the combination therapies are administered at 1 minute to 24 hours apart.
  • alkyl refers to straight chained and branched saturated Ci_io hydrocarbon groups , including but not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, and t-butyl.
  • C n means the alkyl group has "n" carbon atoms.
  • An alkyl, e.g., methyl, group can be substituted with one or more, and typically one to three, of independently selected halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, nitro, cyano, alkylamino, or amino groups, for example.
  • halo is defined as fluoro, chloro, bromo, and iodo.
  • alkoxy is defined as— OR, wherein R is alkyl.
  • amino is defined as— NH 2
  • alkylamino is defined as — NR 2 , wherein at least one R is alkyl and the second R is alkyl or hydrogen.
  • cyano is defined as— CN.
  • trifluoromethyl is defined as— CF 3 .
  • trifluoromethoxy is defined as— OCF 3 .
  • aryl refers to a monocyclic or polycyclic aromatic group, preferably a monocyclic or bicyclic aromatic group.
  • aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl.
  • Aryl also refers to bicyclic and tricyclic carbon rings, where one ring is aromatic and the others are saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl).
  • an aryl group can be unsubstituted or substituted with one or more, and in particular one to four, groups independently selected from, for example, halo, alkyl, alkenyl, — OCF 3 ,— N0 2 ,— CN,— NC,—OH, alkoxy, amino, alkylamino,— C0 2 H,—
  • heterocyclic refers to a heteroaryl and heterocycloalkyl ring systems.
  • heteroaryl refers to a monocyclic or bicyclic ring system containing one or two aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring.
  • Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of
  • heteroatoms in each ring is four or less and each ring contains at least one carbon atom.
  • the heteroaryl group has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
  • monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl.
  • bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quiazolinyl,
  • a heteroaryl group can be unsubstituted or substituted with one or more, and in particular one to four, substituents selected from, for example, halo, alkyl, alkenyl,— OCF 3 ,— N0 2 ,— CN,— NC,— OH, alkoxy, amino, alkylamino,— C0 2 H,— C0 2 alkyl, -OCOalkyl, aryl, and heteroaryl.
  • cycloalkyl means a monocyclic aliphatic ring containing three to eight carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, optionally substituted with one or more, and typically one to three, of independently selected halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, nitro, cyano, alkylamino, or amino groups, for example.
  • heterocycloalkyl means a monocyclic or a bicyclic aliphatic ring containing 4 to 12 total atoms, of which one to five of the atoms are
  • heterocycloalkyl groups are azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, dihydropyrrolyl, morpholinyl, thiomorpholinyl, dihydropyridinyl, oxacycloheptyl, dioxacycloheptyl, thiacycloheptyl, diazacycloheptyl, each optionally substituted with one or more, and typically one to three, of independently selected halo, Ci_ 6 alkyl, C 1-6 alkoxy, cyano, amino, carbamoyl, nitro, carboxy, C 2 _ 7 alkenyl, C 2 _ 7 alkynyl, or the like on an atom of the ring.
  • the present invention therefore is directed to classes of inhibitors ST2.
  • the compounds bind to ST2 and function as potent antagonists of the ST2/IL33 interaction.
  • the ST2 inhibitors of the present invention therefore are useful in the treatment of a variety of diseases and conditions, including GVHD and autoimmune diseases, in subjects in need of such treatment, comprising administering a therapeutically effective amount of a compound of embodiments (I)-(IV).
  • the present invention is directed to the following embodiments: [0096] (I) A compound having a structural formula (I)
  • R 1 is selected from the group consisting of R b , -Ci_ 3 alkyl , substituted or unsubstituted heteroaryl, substituted and unsubstituted aryl,
  • R is selected from the group consisting of
  • R a is H, substituted or unsubstituted aryl, or Ci_ 4 alkyl
  • R b is H, substituted or unsubstituted aryl, optionally
  • R c is Ci_ 3 alkyl, -(CH 2 )i_ 3 OCi_ 3 alkyl, -(CH 2 )i_ 3 C0 2 H, substituted or unsubstituted
  • R d is substituted or unsubstituted aryl, -(CH 2 )i_ 3 OCi_ 4 alkyl, -(CH 2 )i_ 3 heteroaryl, and -(CH 2 )i_ 3 heterocycloalkyl;
  • n O or l
  • R° is -N0 2 , halo, or -CN
  • R e is H or -C M alkyl
  • Z is null, NR 5 or S ;
  • D is -CH 2 - or /
  • R 4 is phenyl, heteroaryl, -(CH 2 )i_ 2 heteroaryl, cycloalkyl,
  • heterocycloalkyl -C 6 H 5 -0-R h , -(CH 2 )i- 2 -C 6 H5, or -(CH 2 ) ! _ 3 OR h ;
  • R 5 is null, H, or -(CH 2 )i- 3 OR h , or
  • R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a heteroaryl group or a substituted or unsubstituted heterocycloalkyl group;
  • R g is H or halo
  • R h is H or Ci_ 3 alkyl, or [0123] a pharmaceutically acceptable salt thereof.
  • R' is ethyl, optionally substituted with
  • R° is N0 2 , CN, CI, or F.
  • R 3 is
  • Z is NCH 2 CH 2 OH and R 4 is -CH 2 CH 2 OH; [0133] or Z is null and R 4 is H or C 6 H 5 .
  • compositions of the invention can exist as salts.
  • Pharmaceutically acceptable salts of the compounds of the invention often are preferred in the methods of the invention.
  • pharmaceutically acceptable salts refers to salts or zwitterionic forms of the compounds of structural formula (I). Salts of compounds of formula (I) can be prepared during the final isolation and purification of the compounds or separately by reacting the compound with an acid having a suitable cation.
  • the pharmaceutically acceptable salts of compounds of structural formula (I) can be acid addition salts formed with pharmaceutically acceptable acids.
  • acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.
  • Nonlimiting examples of salts of compounds of the invention include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hy-droxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerolphsphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylene-sulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylprop
  • any reference to compounds of the present invention appearing herein is intended to include compounds of embodiments (I)-(VI) as well as pharmaceutically acceptable salts, hydrates, or solvates thereof.
  • a combined library of small molecules was used in the high throughput screening experiment adopting the AlphaLISA assay.
  • the AlphaLISA assay was developed to detect the inhibition between IL-33(with donor beads) and human ST2-Fc chimera (with acceptor beads). From the primary screening, compounds yielding greater than 30% of inhibition at 17 ⁇ were selected for structural analysis.
  • Molecular ACCess System (MACCS) fingerprints of compounds were employed in the structural cluster analysis using a 70% similarity threshold to separate groups. Each group was manually inspected to eliminate false positives including reported frequent binders and structures belonging to pan-assay interference compounds (PAINS) (Baell, J. B. & Holloway, G. A.
  • PAINS pan-assay interference compounds
  • the activities of the compounds was observed by their inhibition to the binding between IL-33 in media and ST2 over-expressed on the HEK-BLUE cells monitored by the intracellular activation of NF-kB to release the SEAP reporter proteins. Compounds then were selected for a hit- enrichment study.
  • PE Donor Beads (5mg/ml stock)
  • %Inh [(Ave. signal of no-compound-controls - Ave. signal of no protein controls) - signal of compound)] / (Ave. signal of no-compound-controls - Ave. signal of no protein controls)
  • HEK-Blue IL-33/IL-1B Cells in culture [0224] Zeocin ( 1 OOmg/ml) : stored at -20C [0225] Blasticidin (lOmg/ml): stored at -20C [0226] HygroGold: stored at -20C
  • Normocin 50mg/ml: formulation of three antibiotics active against mycoplasmas, bacteria and fungi. Stored at -20°C.
  • T-75 flask for culturing cells [0237] Compounds to be tested: 200 mM stock of each, except 4073-0156 and C226-3822 which are stocked at 100 mM
  • huIL-33 10 ng/ul stock stored at -80°C
  • huTNFa 10 ug/ml stock stored at -80°C
  • DMEM 4.5 g/1 glucose, 10% (v/v) fetal bovine serum, 50U/ml penicillin, 50ug/ml streptomycin, lOOug/ml Normocin, 2mM L-glutamine
  • DMEM 4.5 g/1 glucose, 10% (v/v) heat-inactivated fetal bovine serum, 50U/ml penicillin, 50ug/ml streptomycin, lOOug/ml Normocin, 2mM L-glutamine
  • Filter reconstituted QUANTI-Blue on a 0.2um membrane in a sterile 250ml bottle.
  • Reconstituted detection medium immediately or store at 4°C.
  • Reconstituted QUANTI-Blue is stable for at least 2weeks when properly stored.
  • [0260] 1) Prepare 2 type of media : [0261] Growth medium (DMEM, 4.5 g/1 glucose, 10% (v/v) fetal bovine serum, 50U/ml penicillin, 50ug/ml streptomycin, lOOug/ml Normocin, 2mM L-glutamine) 5 ml
  • ST2 inhibitors shown below were tested in vitro and in vivo to evaluate their efficacy in the ST2 Inhibition in cells and mouse models.
  • the in vitro human mixed leukocytes allogeneic reaction data showed that ST2 Inhibitor 1 and 3 are effective in reducing the production of IFN-g in CD4+ and CD8+ T cells while maintaining the regulatory T cells population, compared to the DMSO treated control.
  • ST2 Inhibitor 2 did not show efficacy in these tests (Figs. 1-2).
  • mice transplanted with human T cells to establish xenogeneic GVHD were treated with 828 ⁇ g of ST2 Inhibitor 1 per dose in 200 ⁇ daily, via intraperitoneal injection, from day-1 to day 20, an improved GVHD score and survival was observed compared to the mice treated with the DMSO control (Fig. 3).
  • ST2 Inhibitor 2 (374 ⁇ g per dose in 200 ⁇ daily) also showed efficacy in these experimental models whereas ST2 inhibitor 4 (408 ⁇ g per dose in 200 ⁇ daily) did not (Fig. 3).
  • the main GVHD target organ collected at Day 14 and 21 after HCT.
  • the plasma mouse ST2 levels of the mice decrease by 4 fold at Day 14 in the ST2 Inhibitor 1 treatment group in reference to the DMSO control whereas the plasma IFNg concentration decreases by 3 fold as compared to the DMSO control (Fig. 15).
  • the efficacy of ST2 Inhibitor 1 to the B6 ⁇ C3H.SW GVHD model is associated with the reduced IFN-g production and inhibition of soluble ST2 reflected in the reduced plasma ST2 levels.
  • ST2 Inhibitor 1 ST2 Inhibitor 2 ST2 Inhibitor 3 ST2 Inhibitor 4
  • FIGS show the efficacy of the present ST2 inhibitors in in vitro and in vivo GVHD models.
  • FIG. 1 summarizes CD4 and CD8 T cell proliferation measured by CFSE dilution and IFN- ⁇ production measured by intracellular staining in mixed leukocyte reactions with DMSO or ST2 inhibitors.
  • FIG. 1 shows that ST2 inhibitors reduce type 1 cells proliferation in human mixed lymphocyte reaction.
  • FIG. 2 shows that ST2 inhibitors preserve Treg cells in human mixed lymphocyte reaction.
  • NSG mice were transplanted with human T cells (10 6 ) after 300 cGy total body irradiation on day-1.
  • DMSO or an ST2 inhibitor was administered via intraperitoneal injection daily from day -1 to day 20 after HCT.
  • GVHD score and survival are shown.
  • n 13 per group. **p ⁇ 0.01, ***p ⁇ 0.001.
  • Fig. 4 shows the percentage population of human IFNg+ CD4+ T cells and human Foxp3+ CD4+ Treg cells in live human CD45+CD4+ T cells collected from the gut after DMSO and ST2 inhibitors treatment at day 14 in the NSG mice.
  • Fig. 5 shows the percentage population of human IFNg+ CD4+ T cells and human Foxp3+ CD4+ Treg cells in live human CD45+CD4+ T cells collected from the gut after DMSO and ST2 inhibitors treatment at day 21 in the NSG mice.
  • FIGS. 7-13 C3H.SW mice were transplanted with B57BL/6 bone marrow (5 xlO 6 ) and T cells (2 x 10 6 ) after 1100 cGy total body irradiation on day-1.
  • DMSO or an ST2 inhibitor was administered via intra-peritoneal injection daily from day -1 to day 20 after HCT. GVHD score and survival are shown.
  • n 13 per group from two experiments. **p ⁇ 0.01, ***p ⁇ 0.001.
  • Fig. 14 shows the percentage (expressed in mean + standard error of the mean) population of C3H.SW mouse IFN-y+, T-bet+, RORgt+ T cells and Foxp3+ CD4+ Treg cells in CD4+ T cells collected from the gut after DMSO or ST2 inhibitor treatment at day 14 in the C3H.SW mice. On day 21, IL-4+ and Gata3+ CD4+ T cell population are also analyzed.
  • the compounds of embodiments (I)-(IV) inhibit ST2 and are useful in the treatment of a variety of diseases and conditions.
  • the compounds of embodiments (I)-(IV) are used in methods of treating a disease or condition wherein inhibition of ST2 provides a benefit, for example, GVHD and asthma.
  • the method comprises administering a
  • the present methods also encompass administering a second therapeutic agent to the individual in addition to the compound of embodiments (I)- (IV).
  • the second therapeutic agent is selected from drugs known as useful in treating the disease or condition afflicting the individual in need thereof, e.g., a chemotherapeutic agent and/or radiation known as useful in treating a hematological cancer.
  • compositions for use in accordance with the present invention are formulated in a conventional manner using one or more
  • physiologically acceptable carriers comprising excipients and auxiliaries that facilitate processing of compounds of embodiments (I)-(IV).
  • a second therapeutically active agents one or more of which can be used in combination with an ST2 inhibitor of embodiments (I)- (IV), are prepared and administered as described in the art.
  • compositions can be manufactured, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping, or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen.
  • a therapeutically effective amount of the compound of embodiments (I)-(IV) is administered orally, the composition typically is in the form of a tablet, capsule, powder, solution, or elixir.
  • the composition typically is in the form of a tablet, capsule, powder, solution, or elixir.
  • composition additionally can contain a solid carrier, such as a gelatin or an adjuvant.
  • a solid carrier such as a gelatin or an adjuvant.
  • the tablet, capsule, and powder contain about 0.01% to about 95%, and preferably from about 1% to about 50%, of a compound of embodiments (I)-(IV).
  • a liquid carrier such as water, petroleum, or oils of animal or plant origin, can be added.
  • the liquid form of the composition can further contain physiological saline solution, dextrose or other saccharide solutions, or glycols.
  • the composition contains about 0.1% to about 90%, and preferably about 1% to about 50%, by weight, of a compound of embodiments (I)-(IV).
  • composition When a therapeutically effective amount of a compound of embodiments (I)-(IV) is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution.
  • parenterally acceptable solutions having due regard to pH, isotonicity, stability, and the like, is within the skill in the art.
  • a preferred composition for intravenous, cutaneous, or subcutaneous injection typically contains, an isotonic vehicle.
  • Compounds of embodiments (I)-(IV) can be readily combined with pharmaceutically acceptable carriers well-known in the art.
  • Such carriers enable the active agents to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by adding the compound of embodiments (I)-(IV) to a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients include, for example, fillers and cellulose preparations. If desired, disintegrating agents can be added.
  • a compound of embodiments (I)-(IV) can be formulated for parenteral
  • Formulations for injection can be presented in unit dosage form, e.g., in ampules or in multidose containers, with an added preservative.
  • the compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form.
  • suspensions of a compound of embodiments (I)-(IV) can be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters.
  • Aqueous injection suspensions can contain substances which increase the viscosity of the suspension.
  • the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds and allow for the preparation of highly concentrated solutions.
  • a present composition can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a compound of embodiments (I)-(IV) also can be formulated in rectal
  • compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases.
  • the compound of embodiments (I)-(IV) also can be formulated as a depot preparation.
  • Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds of embodiments (I)-(IV) can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins.
  • the compounds of embodiments (I)-(IV) can be administered orally, buccally, or sublingually in the form of tablets containing excipients, such as starch or lactose, or in capsules or ovules, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
  • excipients such as starch or lactose
  • capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
  • Such liquid preparations can be prepared with pharmaceutically acceptable additives, such as suspending agents.
  • the compounds of embodiments (I)-(IV) also can be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily.
  • the present ST2 inhibitors are best used in the form of a sterile aqueous solution which can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood.
  • a sterile aqueous solution which can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood.
  • kits which comprise one or more compounds or compositions packaged in a manner that facilitates their use to practice methods of the invention.
  • the kit includes a compound or composition described herein as useful for practice of a method (e.g., a composition comprising a compound of embodiments (I)-(IV) and an optional second therapeutic agent), packaged in a container, such as a sealed bottle or vessel, with a label affixed to the container or included in the kit that describes use of the compound or composition to practice the method of the invention.
  • the compound or composition is packaged in a unit dosage form.
  • the kit further can include a device suitable for administering the composition according to the intended route of administration.
  • Prior ST2 inhibitors possessed properties that hindered their development as therapeutic agents.
  • compounds of embodiments (I)-(IV) were evaluated as inhibitors for ST2.
  • compounds of the present invention typically have a bonding affinity (IC 50 ) to ST2 of less than 500 ⁇ , less than 100 ⁇ , less than 50 ⁇ , and less than 25 ⁇ .

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Abstract

L'invention concerne des composés capables d'inhiber la suppression de la tumorigénicité 2 (ST2). Les composés sont utiles dans le traitement de diverses maladies et affections, telles que l'atténuation de la réaction du greffon contre l'hôte (GVHD), les maladies cardio-vasculaires, l'asthme, le lupus, et d'autres maladies inflammatoires liées à un déséquilibre Th1/Th2.
PCT/US2016/060890 2015-11-13 2016-11-08 Inhibiteurs de la suppression de la tumorigénicité 2 (st2) et leurs procédés d'utilisation Ceased WO2017083242A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008144610A1 (fr) 2007-05-18 2008-11-27 Medimmune, Llc Il-33 dans une maladie inflammatoire
WO2013173761A2 (fr) 2012-05-18 2013-11-21 Amgen Inc. Protéines de liaison à l'antigène st2

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008144610A1 (fr) 2007-05-18 2008-11-27 Medimmune, Llc Il-33 dans une maladie inflammatoire
WO2013173761A2 (fr) 2012-05-18 2013-11-21 Amgen Inc. Protéines de liaison à l'antigène st2

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BAELL, J. B.; HOLLOWAY, G. A.: "New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays", J MED CHERN, vol. 53, 2010, pages 2719 - 2740
BANERJEE MONIMOY ET AL: "Differential regulation of CYP3A4 promoter activity by a new class of natural product derivatives binding to pregnane X receptor", BIOCHEMICAL PHARMACOLOGY, vol. 86, no. 6, 2013, pages 824 - 835, XP028707033, ISSN: 0006-2952, DOI: 10.1016/J.BCP.2013.07.023 *
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FUNG-YI CHAN ET AL: "Identification of a New Class of FtsZ Inhibitors by Structure-Based Design and in Vitro Screening", JOURNAL OF CHEMICAL INFORMATION AND MODELING, vol. 53, no. 8, 26 August 2013 (2013-08-26), US, pages 2131 - 2140, XP055338059, ISSN: 1549-9596, DOI: 10.1021/ci400203f *
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