P450 interaction with HIV protease inhibitors: relationship between metabolic stability, inhibitory potency, and P450 binding spectra.
More than 60 human immunodeficiency virus protease inhibitors were examined for the structure-activity relationship between metabolic stability, CYP3A4 inhibitory potency, and substrate-induced binding spectra with a ferric form of P450 in human liver microsomes. A positive relationship was found between CYP3A4 inhibitory potency and metabolic stability; namely, compounds that were more potent for the CYP3A4 inhibition generally were more metabolically stable. In addition, the compounds formed two clusters defined by the distinct type of substrate-induced P450 binding spectra: the compounds with type II binding spectra were more stable metabolically and more potent for the CYP3A4 inhibition than those with type I binding spectra. The structure-activity relationship suggested that the presence and position of heterocyclic nitrogen on the pyridine moiety play an important role in determining the manner of interaction with P450 and the magnitude of CYP3A4 inhibition/metabolic stability in the series of structurally related human immunodeficiency virus protease inhibitors under development.
Chiba
M
M
Department of Drug Metabolism, West Point, Pennsylvania, USA. chibam@banyu.co.jp
Jin
L
L
Neway
W
W
Vacca
J P
JP
Tata
J R
JR
Chapman
K
K
Lin
J H
JH
D019380:Anti-HIV Agents / Q000378:metabolism* / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011485:Protein Binding; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human