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

ABSTRACT: 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.

SUBMITTER: Wilson KJ 

PROVIDER: S-EPMC6102074 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Wilson Kenneth J KJ   Xiao Jingbo J   Chen Catherine Z CZ   Huang Zaohua Z   Agoulnik Irina U IU   Ferrer Marc M   Southall Noel N   Hu Xin X   Zheng Wei W   Xu Xin X   Wang Amy A   Myhr Courtney C   Barnaeva Elena E   George Emmett R ER   Agoulnik Alexander I AI   Marugan Juan J JJ  

European journal of medicinal chemistry 20180607

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 hig  ...[more]

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