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Bioorg Med Chem Lett. 2010 Sep 1;20(17):5074-9. doi: 10.1016/j.bmcl.2010.07.030. Epub 2010 Jul 11.

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

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Merck Frosst Centre for Therapeutic Research, Kirkland, Québec, Canada.


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.

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