Structure–Activity Relationship Studies toward the Optimization of First-In-Class Selective Small Molecule Agonists of the GPCR Relaxin/Insulin-like Family Peptide Receptor 2

Year: 2026

Type: article

Abstract: A dose–response quantitative high-throughput screening of 147,334 small molecule compounds using a human Relaxin/Insulin-like Family Peptide Receptor 2 (RXFP2)-transfected HEK293T-RXFP2 cell line identified compound 5 with modest Insulin-Like3 (INSL3) agonist activity. An extensive structure–activity relationship (SAR) study was undertaken to improve potency, efficacy, and physical/metabolic properties of the series, resulting in the discovery of compound 68 . This compound represents the first-in-class small molecule full agonist of RXFP2 that exhibits nanomolar potency and favorable pharmacokinetic characteristics, including high systemic exposure in vivo. Based on these findings, compound 68 was selected as the lead preclinical candidate for investigating the role of RXFP2 activation in bone remodeling and other physiological systems in vitro and in vivo .

Source: Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.5c03387

Institutions: National Institutes of Health, National Center for Advancing Translational Sciences, Florida International University, The Ohio State University, University of South Florida

Language: English

Topic: Pregnancy-related medical research

Subfield: Public Health, Environmental and Occupational Health

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Advancing Translational Sciences

Awards: G2521981138, G9000153366

OpenAlex ID: W7130502360