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-9452973-B2
Publication Date
2016-09-27
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, specifically compounds of formula (I) and their pharmaceutically acceptable salts. These modulators are designed to treat mammalian relaxin receptor 1 mediated facets of human health, such as cardiovascular disease. The invention encompasses pharmaceutical compositions comprising these compounds and methods for therapeutic intervention in mammalian health conditions mediated by the human relaxin receptor 1.
The background identifies the peptide hormone relaxin's role in pregnancy-related physiological changes, including promoting cardiovascular and renal adjustments. Relaxin works through activation of the relaxin receptor 1 (RXFP1), a G protein-coupled receptor, modulating pathways that lead to vasodilation, extracellular matrix remodeling, inflammation moderation, and angiogenesis. Despite recombinant relaxin's positive clinical responses, its peptide nature poses administration challenges in chronic settings, creating an unmet need for small molecule agonists of RXFP1.
Claims Coverage
The claims include three independent claims covering compounds of formula (I), pharmaceutical compositions containing these compounds, and methods for treating relaxin receptor 1 mediated conditions.
compounds modulating human relaxin receptor 1
Compounds or pharmaceutically acceptable salts of formula (I) characterized by specific structural features including A as 1,2-phenylenyl, 1,2-heteroarylenyl, 1,2-heterocyclyl, or —CH2CH2—; substituents R1, R2, R3, R4, R5, R6, and R7 defined by multiple optional groups and substituents. The formula includes provisos restricting combinations of R3, A, and R2 to avoid certain substitutions.
pharmaceutical compositions
Pharmaceutical compositions comprising a compound or salt of formula (I) and a pharmaceutically acceptable carrier suitable for various modes of administration such as parenteral, topical, oral, pulmonary, and others.
method of therapeutic intervention
A method for treating mammalian health facets mediated by relaxin receptor 1 by administering a therapeutically effective amount of a compound or salt of formula (I), including cardiovascular diseases, fibrosis, respiratory and skin diseases, cancer, reproductive disorders, and others.
The independent claims focus on novel chemical compounds targeting human relaxin receptor 1, formulations for their delivery, and therapeutic methods for intervening in multiple diseases mediated by RXFP1. The inventive features emphasize specific structural formulas, pharmaceutical preparations, and broad therapeutic applications.
Stated Advantages
Compounds exhibit relaxin-like pharmacological effects including cardiovascular and renal modulation.
Small molecule modulators provide an alternative to peptide relaxin with potentially improved chronic administration.
Compounds demonstrate ability to activate target receptor and downstream signaling pathways such as cAMP production and VEGF expression.
Pharmaceutical compositions allow multiple routes of administration suitable for various clinical needs.
Certain compounds show potency, selectivity, and favorable pharmacokinetic profiles, including oral bioavailability and metabolic stability.
Documented Applications
Treatment of cardiovascular diseases including acute heart failure, myocardial ischemia, hypertension, and related conditions.
Therapeutic intervention for fibrotic diseases such as pulmonary fibrosis, renal fibrosis, hepatic fibrosis, and scleroderma.
Treatment of respiratory diseases including asthma, COPD, ARDS, severe acute respiratory syndrome, and cystic fibrosis.
Management of skin diseases including wound healing, burns, psoriasis, lupus, and collagenous disorders.
Female reproductive applications including in vitro fertilization, preterm birth, placental defects, preeclampsia, and labor complications.
Male reproductive therapies targeting sperm function and fertilization.
Improvement in surgical transplantation outcomes, especially liver.
Cancer treatment including various cancers and enhancement of drug or radiation delivery.
Orthodontic tooth movement facilitation.
Treatment of bone and joint diseases such as osteoporosis, osteoarthritis, osteopetrosis, osteosarcoma and bone metastasis.
Diabetes mellitus management.
Treatment of ischemia-reperfusion injury in multiple organs and conditions.
Treatment of inflammatory and autoimmune disorders including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and transplant rejection.
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