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

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.