Addressing time-dependent CYP 3A4 inhibition observed in a novel series of substituted amino propanamide renin inhibitors, a case study

Time-dependent inhibitors of CYPs have the potential to perpetrate drug–drug interactions in the clinical setting. After finding that several leading compounds in a novel series of substituted amino propanamide renin inhibitors inactivated CYP3A4 in an NADPH-dependent and time-dependent manner, a search to identify the cause of this liability was initiated. Extensive SAR revealed that the amide bridge present in compound 1 as a possible culprit. Through the installation of a metabolic soft spot distal to this moiety, potent renin inhibitors with improved CYP profile were identified.

Graphical abstractThe identification of a possible culprit responsible for compound (1)’s time-dependent CYP 3A4 inhibition as well as suitable solution are described therein.Figure optionsDownload full-size imageDownload as PowerPoint slide