BMP inhibitors and methods of use thereof
Inventors
Alimardanov, Asaf • Cuny, Gregory D. • Grewal, Gurmit Singh • Lee, Arthur • McKew, John C. • Mohedas, Agustin H. • Shen, Min • Xu, Xin • Yu, Paul B.
Assignees
Brigham and Womens Hospital Inc • National Institutes of Health NIH • US Department of Health and Human Services
Publication Number
US-9682983-B2
Publication Date
2017-06-20
Expiration Date
2034-03-13
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Abstract
The present invention provides small molecule inhibitors of BMP signaling. These compounds may be used to modulate cell growth, differentiation, proliferation, and apoptosis, and thus may be useful for treating diseases or conditions associated with BMP signaling, including inflammation, cardiovascular disease, hematological disease, cancer, and bone disorders, as well as for modulating cellular differentiation and/or proliferation. These compounds may also be used to reduce circulating levels of ApoB-100 or LDL and treat or prevent acquired or congenital hypercholesterolemia or hyperlipoproteinemia; diseases, disorders, or syndromes associated with defects in lipid absorption or metabolism; or diseases, disorders, or syndromes caused by hyperlipidemia.
Core Innovation
The invention provides small molecule inhibitors of BMP signaling that are capable of modulating cell growth, differentiation, proliferation, and apoptosis. These compounds are designed to inhibit BMP-induced phosphorylation of SMAD1/5/8 and can be used to treat diseases or conditions associated with BMP signaling, such as inflammation, cardiovascular disease, hematological disease, cancer, and bone disorders. They are also useful for modulating cellular differentiation and proliferation, and for reducing circulating levels of ApoB-100 or LDL to treat conditions like hypercholesterolemia or hyperlipoproteinemia.
The problem addressed by the invention stems from the complexity and diversity of the BMP and TGF-β superfamily signaling system. Traditional approaches for inhibiting BMP signals, such as soluble receptors, endogenous inhibitors, or neutralizing antibodies, are impractical or ineffective due to limited specificity, low affinity, and structural diversity. There is a need for pharmacologic agents that specifically antagonize BMP signaling pathways to manipulate these pathways therapeutically or experimentally.
Claims Coverage
The patent discloses one independent claim specifically related to compounds of Formula I, with additional related claims covering pharmaceutical compositions and methods of treatment.
Compound having a structure of Formula I or pharmaceutically acceptable derivatives
A compound characterized by the specific chemical structure of Formula I or its pharmaceutically acceptable salts, esters, or prodrugs, defined by particular substituents and ring systems including variations of heteroatoms and substituents such as Ar, L1, R4, and pattern restrictions on nitrogen atoms.
Substituent selection for improved activity
Specific substituent configurations where B is C—R25 when E is N or K is C—R25 when M is N, with R25 selected from groups like deuterium, halogens, alkyls, hydroxyl, and methoxy, leading to particular compound properties.
Selection of nitrogen-containing heteroaryl groups for Ar
Ar group can be a substituted or unsubstituted nitrogen-containing heteroaryl selected from pyridine, pyrazine, pyrimidine, oxazole, thiazole, or thiadiazole with specified substituents enhancing activity or selectivity.
Placement and nature of substituents on Ar and L1
Substituents are strategically placed on Ar, such as para-position relative to the bicyclic core, with L1 being absent or having specified structures, influencing compound properties.
Pharmaceutical composition comprising the compound
A pharmaceutical composition includes at least one compound of Formula I together with pharmaceutically acceptable excipients or solvents suitable for administration.
Method of treating diseases benefiting from BMP inhibition
Methods of treating diseases or conditions benefiting from BMP signaling inhibition by administering the compound, targeting conditions such as pulmonary hypertension, hereditary hemorrhagic telangiectasia, fibrodysplasia ossificans progressiva, anemia, atherosclerosis, various cancers, inflammatory disorders, infections, and bone disorders.
Method of reducing circulating ApoB-100 and LDL levels
Method to reduce circulating levels of ApoB-100 and/or LDL or total cholesterol to reduce the risk of cardiovascular events by administering the compound.
Method of treating lipid disorders and hepatic steatosis
Method of treating hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hepatic steatosis including both congenital and acquired forms, and associated diseases by administering the compound.
The independent claim focuses on a defined chemical compound structure capable of inhibiting BMP signaling with specific substituent patterns and heteroaryl groups, supported by claims on pharmaceutical compositions and therapeutic methods covering treatment of multiple diseases and lipid disorders.
Stated Advantages
The compounds provide specific antagonism of BMP signaling, overcoming limitations of traditional BMP inhibitors.
They offer improved in vivo efficacy by mitigating metabolic liabilities identified in prior compounds, such as formation of reactive metabolites or inactive oxidized products.
BMP inhibitors described can modulate a wide range of biological processes including cell growth, differentiation, and apoptosis, enabling treatment of diverse diseases.
Compounds reduce circulating levels of ApoB-100 and LDL, providing a novel mechanism to treat or prevent hypercholesterolemia, hyperlipoproteinemia, and cardiovascular events.
Documented Applications
Treatment or prevention of diseases or conditions benefiting from BMP signaling inhibition, including pulmonary hypertension, hereditary hemorrhagic telangiectasia syndrome, cardiac valvular and structural malformations, fibrodysplasia ossificans progressiva, juvenile familial polyposis syndrome, parathyroid disease, anemia, vascular calcification, atherosclerosis, valve calcification, renal osteodystrophy, ankylosing spondylitis, vascular inflammation, inflammatory bowel disease, psoriasis, and infections caused by viruses, bacteria, fungi, tuberculosis, and parasites.
Treatment of various cancers, such as breast carcinoma, prostate carcinoma, renal cell carcinoma, bone metastasis, lung metastasis, osteosarcoma, and multiple myeloma.
Methods to reduce circulating levels of ApoB-100 and LDL to mitigate risk of cardiovascular events.
Treatment of hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hepatic steatosis, including both congenital (e.g., familial hypercholesterolemia) and acquired forms associated with lifestyle or disease states.
Use in modulating cellular differentiation, expansion, or de-differentiation of pluripotent or adult stem cells in vitro or in vivo.
Potential use in combination therapies with other drugs for synergistic or additive effects in metabolic, cardiovascular, inflammatory, and oncologic conditions.
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