Discovery of a highly selective CYP3A4 inhibitor suitable for reaction phenotyping studies and differentiation of CYP3A4 and CYP3A5.

ABSTRACT: Current molecular tools lack the ability to differentiate the activity of CYP3A4 and CYP3A5 in biological samples such as human liver microsomes. Kinetic experiments and the CYP3A4 crystal structure indicate that the active sites of both enzymes are large and flexible, and have more than one binding subsite within the active site. 1-(4-Imidazopyridinyl-7phenyl)-3-(4'-cyanobiphenyl) urea (SR-9186) was optimized through several rounds of structural refinement from an initial screening hit to obtain greater than 1000-fold selectivity for the inhibition of CYP3A4 versus CYP3A5. Characterization data demonstrate selectivity using midazolam and testosterone hydroxylation assays with recombinant cytochrome P450, pooled human liver microsomes, and individually genotyped microsomes. Clear differenc

SUBMITTER: Li X 

PROVIDER: S-EPMC3422543 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature