1区 · 医学
Article
作者: Wu, Yong-Jin ; Harden, David ; Sun, Li-Qiang ; Davis, Carl D. ; Newton, Amy E. ; Dworetzky, Steven ; Zoeckler, Mary ; Fitzpatrick, William C. ; Sinz, Michael W. ; Polson, Craig ; Sivarao, Digavalli V. ; He, Huan ; Philip, Thomas ; Weaver, David ; Yeola, Suresh ; Tertyshnikova, Svetlana ; Knox, Ronald J.
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.