NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA.
Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th Street, HLSI 419B, Miami, FL, 33199, USA.
Eur J Med Chem. 2018 Aug 5;156:79-92. doi: 10.1016/j.ejmech.2018.06.008. Epub 2018 Jun 7.
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.
一种针对人类松弛素/胰岛素样家族肽受体（RXFP1）转染的 HEK293 细胞系的>350,000 种化合物的剂量反应定量高通量筛选（qHTS）发现了具有适度激动活性的 2-乙酰氨基-N-苯基苯甲酰胺 1 和 3。已经进行了广泛的构效关系研究，以优化该系列的效力、功效和物理性质，从而鉴定出化合物 65（ML-290），其具有优异的体内 PK 特性和高水平的全身暴露。该系列以 65 为代表，产生了 RXFP1 的一流小分子激动剂，是抗纤维化基因的有效激活剂。
