Modulators of the relaxin receptor 1
Inventors
Marugan, Juan Jose • Xiao, Jingbo • Ferrer-Alegre, Marc • Chen, Catherine • Southall, Noel • Zheng, Wei • Agoulnik, Alexander • Agoulnik, Irina
Assignees
Florida International University FIU • US Department of Health and Human Services
Publication Number
US-10125112-B2
Publication Date
2018-11-13
Expiration Date
2033-03-15
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Abstract
Disclosed are modulators of the human relaxin receptor 1, for example, of formula (I), wherein A, R1, and R2 are as defined herein, that are useful in treating mammalian relaxin receptor 1 mediated facets of human health, e.g., cardiovascular disease. Also disclosed is a composition comprising a pharmaceutically suitable carrier and at least one compound of the disclosure, and a method for therapeutic intervention in a facet of mammalian health that is mediated by a human relaxin receptor 1.
Core Innovation
The invention provides modulators of the human relaxin receptor 1, exemplified by compounds of formula (I) with defined substituent groups A, R1, R2, and others as detailed. These modulators are useful in treating facets of mammalian health mediated by relaxin receptor 1 such as cardiovascular disease.
The problem solved arises from the limitations of current therapies for cardiovascular diseases, especially acute heart failure (AHF). Current treatments do not address the development of scar heart tissue or repair it after damage. The peptide hormone relaxin has shown pharmacological utility in modulating cardiovascular and renal functions, but recombinant relaxin hormone, being a peptide, is difficult to administer in chronic settings. Thus, there is an unmet need for new small molecule agonists of the RXFP1 receptor that can provide the beneficial effects of relaxin.
Claims Coverage
The patent contains multiple claims, with independent claims focusing on novel compounds of formula (I), methods for therapeutic intervention using these compounds, and compositions thereof. The main inventive features include novel chemical structures, therapeutic methods, and specific substituent definitions.
Novel compounds of formula (I)
Compounds and pharmaceutically acceptable salts characterized by formula (I) having defined substituents A, R1, R2, R3, R4, R5, R6, and R7, with various optional and specific substitutions covering heteroarylenyl, heterocyclyl groups, and specific substituent groups such as halo, CF3, alkyl, alkyloxy, and others.
Pharmaceutical compositions including compounds or salts
Pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one compound or salt of formula (I). The carriers may be suitable for various administration routes such as oral, parenteral, topical, inhalation, and others.
Therapeutic methods for intervention
Methods for therapeutic intervention in mammalian health facets mediated by relaxin receptor 1 by administering an effective amount of a compound or salt of formula (I). In some claims, the mammal is human and the condition includes heart failure and related cardiovascular diseases.
The independent claims cover the novel chemical compounds with defined substituents, the pharmaceutical compositions containing these compounds, and methods for therapeutic intervention targeting relaxin receptor 1 mediated conditions, especially cardiovascular disease such as heart failure.
Stated Advantages
The compounds have anti-fibrotic and remodeling properties, with capacity to normalize blood pressure, increase blood and renal flow, promote decongestion and vascular compliance.
Compounds provide cardiovascular and renal protective effects similar to relaxin but with easier administration, suitable for chronic settings.
Certain compounds demonstrate greater upregulation of VEGF gene expression than relaxin, indicating potential enhanced therapeutic effects.
The compounds selectively activate human relaxin receptor 1 and not related receptors, indicating specificity that may reduce side effects.
Documented Applications
Treatment of cardiovascular diseases including acute heart failure, myocardial ischemia-reperfusion injury, cardiac fibrosis, acute congestive heart failure, cerebrovascular disease, stroke, systemic and pulmonary hypertension, vascular inflammation, left ventricular hypertrophy, and other related conditions.
Treatment of fibrotic diseases such as pulmonary fibrosis, renal tubulointerstitial fibrosis, hepatic fibrosis including cirrhosis, scleroderma, and wound healing associated with diabetes.
Treatment of respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), cystic fibrosis.
Management of skin diseases including dermal repair, wound healing, burns, psoriasis, lupus, scleroderma, and skin tumors.
Improvement of female reproduction-related conditions such as in vitro fertilization success, abnormal implantation, induction of labor, preeclampsia, and uterine fibroids.
Treatment of male reproductive dysfunctions related to sperm function and fertilization.
Use in surgical transplantation of the liver.
Cancer treatment including colon, lung, breast, prostate, brain, pancreatic, and other cancers, and enhancement of drug delivery in solid tumors.
Orthodontic tooth movement and treatment of bone joint diseases including osteoporosis, osteoarthritis, osteopetrosis, and bone cancer.
Diabetes mellitus treatment.
Treatment of ischemia-reperfusion injury associated with stroke, myocardial infarction, peripheral vascular insufficiency, organ transplantation.
Treatment of inflammatory conditions associated with infections such as HIV, AIDS, West Nile virus, coronavirus, influenza virus, and sepsis.
Treatment of kidney diseases including diabetic nephropathy, glomerulosclerosis, nephropathies, and chronic renal failure.
Treatment of angiogenesis-related conditions such as ocular diseases and cancer-associated angiogenesis.
Treatment of autoimmune disorders including multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, and transplant rejection.
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