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 Chemistry
2003.0

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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