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.
Article Details
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Wu YJ, Davis CD, Dworetzky S, Fitzpatrick WC, Harden D, He H, Knox RJ, Newton AE, Philip T, Polson C, Sivarao DV, Sun LQ, Tertyshnikova S, Weaver D, Yeola S, Zoeckler M, Sinz MW
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.
J Med Chem. 2003 Aug 28;46(18):3778-81.
- PubMed ID
- 12930139 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Troleandomycin Cytochrome P450 3A4 IC 50 (nM) 61000 N/A N/A Details Troleandomycin Cytochrome P450 3A4 IC 50 (nM) 33000 N/A N/A Details Troleandomycin Cytochrome P450 3A4 IC 50 (nM) 16000 N/A N/A Details Troleandomycin Cytochrome P450 3A4 IC 50 (nM) 20000 N/A N/A Details