Optimization of the first small-molecule relaxin/insulin-like family peptide receptor (RXFP1) agonists: Activation results in an antifibrotic gene expression profile

A dose responsive quantitative high throughput screen (qHTS) of >350,000 compounds against a human relaxin/insulin-like family peptide receptor (RXFP1) transfected HEK293 cell line identified 2-acetamido-N-phenylbenzamides 1 and 3 with modest agonist activity. An extensive structure-activity study has been undertaken to optimize the potency, efficacy, and physical properties of the series, resulting in the identification of compound 65 (ML-290), which has excellent in vivo PK properties with high levels of systemic exposure. This series, exemplified by 65, has produced first-in-class small-molecule agonists of RXFP1 and is a potent activator of anti-fibrotic genes. [Display omitted] •A high throughput screening campaign identified the first small molecule relaxin peptide hormone receptor agonists.•An extensive medicinal chemistry effort produced an optimized, potent lead compound.•Pharmokinetic studies show good compound bioavailability in mice with no observed toxicity.•The lead compound displays an antifibrotic gene expression profile in activated human hepatic stellate cells.