Fluorine Substitution Can Block CYP3A4 Metabolism-Dependent Inhibition: Identification of (S)-N-[1-(4-Fluoro-3- morpholin-4-ylphenyl)ethyl]-3- (4-fluorophenyl)acrylamide as an Orally Bioavailable KCNQ2 Opener Devoid of CYP3A4 Metabolism-Dependent Inhibition
Journal of Medicinal Chemistry2003Vol. 46(18), pp. 3778–3781
Citations Over TimeTop 10% of 2003 papers
Yong‐Jin Wu, Carl D. Davis, Steven I. Dworetzky, William Fitzpatrick, David Harden, Huan He, Ronald J. Knox, Amy Newton, Thomas Philip, Craig Polson, Digavalli V. Sivarao, Li‐Qiang Sun, Svetlana Tertyshnikova, David T. Weaver, Suresh Yeola, Mary Zoeckler, Michael Sinz
Abstract
The formation of a reactive intermediate was found to be responsible for CYP3A4 metabolism-dependent inhibition (MDI) observed with (S)-N-[1-(3-morpholin-4-ylphenyl)ethyl]-3-phenyl-acrylamide (1). Structure-3A4 MDI relationship studies culminated in the discovery of a difluoro analogue, (S)-N-[1-(4-fluoro-3-morpholin-4-ylphenyl)ethyl]-3-(4-fluoro-phenyl)acrylamide (2), as an orally bioavailable KCNQ2 opener free of CYP3A4 MDI.
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