Compositions and methods for inhibiting BMP
Inventors
Lee, Arthur • McKew, John C. • Patel, Paresma R. • Yu, Paul B. • Mohedas, Agustin H. • Sanderson, Philip E. • Cuny, Gregory D. • Zheng, Wei • Huang, Xiuli
Assignees
Brigham and Womens Hospital Inc • National Institutes of Health NIH • University of Houston System • US Department of Health and Human Services
Publication Number
US-10513521-B2
Publication Date
2019-12-24
Expiration Date
2035-07-14
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Abstract
The present invention provides bicyclic heteroaryl inhibitors of BMP signaling and compositions and methods for inhibiting BMP signaling. Exemplary compounds include those of Formula I:These compounds and compositions 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 and compositions 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 bicyclic heteroaryl inhibitors of BMP signaling and compositions and methods for inhibiting BMP signaling. Exemplary compounds include those of Formula I, as disclosed in the detailed description. These compounds and compositions may be used to modulate cell growth, differentiation, proliferation, and apoptosis. They have potential utility for treating diseases or conditions associated with BMP signaling such as inflammation, cardiovascular disease, hematological disease, cancer, and bone disorders.
The background identifies that signaling involving the TGF-β superfamily, particularly BMP signaling, plays critical roles in various physiological processes including embryogenesis, mesoderm induction, organogenesis, and bone formation. Dysregulation of BMP signaling is implicated in diseases like pulmonary hypertension, hereditary hemorrhagic telangiectasia, fibrodysplasia ossificans progressiva, and juvenile polyposis syndrome. Traditional BMP inhibition approaches, such as using soluble receptors, endogenous inhibitors, or neutralizing antibodies, are limited by the structural diversity and complexity of BMP ligands and receptors, making these methods impractical or ineffective.
Therefore, there is a need for pharmacologic agents that can specifically antagonize BMP signaling pathways with improved specificity and efficacy. The invention addresses this need by providing small molecule compounds, including those of Formula I and II, which inhibit BMP signaling by targeting BMP type I receptors. These compounds display selectivity among ALK kinases involved in BMP signaling, including ALK1, ALK2, ALK3, ALK4, ALK5, and ALK6. The invention also provides methods of inhibiting BMP-induced phosphorylation of SMAD1/5/8, and pharmaceutical compositions containing such compounds.
Claims Coverage
The patent contains multiple independent claims focusing on compounds of Formula I and Formula II and pharmaceutical compositions containing these compounds. The main inventive features relate to the chemical structures of the compounds, their substituents, selective inhibition of BMP signaling via ALK receptors, and pharmaceutical compositions.
Compounds of Formula I and its pharmaceutically acceptable salts
The invention provides compounds having the structure of Formula I or pharmaceutically acceptable salts thereof, including detailed definitions and embodiments of substituents such as R4, R17, L1, J, K, Ar, and others as disclosed in the claims.
Compounds of Formula II and its pharmaceutically acceptable salts
The invention provides compounds having the structure of Formula II or pharmaceutically acceptable salts thereof, with particular substituents and configurations, including specific examples of R17, R20, R21, and structural variations as disclosed.
Selective inhibition of ALK receptors by the compounds
The compounds selectively inhibit ALK2 activity relative to other ALKs such as ALK1, ALK3, ALK4, ALK5, and ALK6, with varying degrees of IC50 values, providing targeted BMP signaling inhibition.
Pharmaceutical compositions comprising the compounds
Pharmaceutical compositions comprising a compound of Formula I or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or solvent for therapeutic use.
The claims cover novel bicyclic heteroaryl compounds represented by Formula I or II with various substituents that selectively inhibit BMP signaling via ALK receptors, especially ALK2, and pharmaceutical compositions containing these compounds. The inventive features emphasize chemical structure variations, selective receptor inhibition, and pharmaceutical compositions, aimed at improving BMP pathway modulation.
Stated Advantages
The compounds provide specific antagonism of BMP signaling pathways with potential for better specificity and reduced toxicity compared to previous methods.
They offer the ability to selectively inhibit ALK kinases with high potency, allowing for therapeutic targeting of BMP-related diseases.
The compounds can be formulated into pharmaceutical compositions suitable for various routes of administration.
Cell-based and enzymatic assays demonstrate robust and selective inhibition of BMP-induced SMAD phosphorylation, indicating effective BMP signaling modulation.
Documented Applications
Treatment or prevention of diseases or conditions associated with BMP signaling including pulmonary hypertension, hereditary hemorrhagic telangiectasia syndrome, cardiac malformations, fibrodysplasia ossificans progressiva, juvenile familial polyposis syndrome, parathyroid disease, cancer, anemia, vascular calcification, atherosclerosis, valve calcification, renal osteodystrophy, inflammatory disorders, and infections.
Methods to reduce circulating ApoB-100, LDL, and total cholesterol to treat or prevent hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, and associated cardiovascular risks.
Treatment of hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, or hepatic steatosis, including acquired forms associated with diabetes mellitus, lifestyle, metabolic syndrome, liver disease, and other disorders.
Treatment of anemia including anemia of chronic disease by inhibiting BMP signaling mediated hepcidin expression.
Modulation of cellular differentiation and proliferation, including expansion or differentiation of embryonic or adult stem cells in vitro or in vivo.
Potential use in preventing and treating pathologic and ectopic bone formation, such as in ankylosing spondylitis, myositis ossificans traumatica, and vascular or valvular calcification.
Use in treatment of psoriasis, skin ulcers, promotion of hair growth, corneal scarring, systemic hypertension, ventricular hypertrophy, neurologic disorders related to inflammation and neurogenesis, and atherosclerosis.
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