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Vol. 29, Issue 1, 1-3, January 2001

SHORT COMMUNICATION
P450 Interaction with HIV Protease Inhibitors: Relationship between Metabolic Stability, Inhibitory Potency, and P450 Binding Spectra

Masato Chiba, Lixia Jin, William Neway, Joseph P. Vacca, James R. Tata, Kevin Chapman, and Jiunn H. Lin

Department of Drug Metabolism
(J.H.L., L.J., M.C., W.N.)
Department of Medicinal Chemistry
(J.P.V.)
Merck Research Laboratories,
West Point, Pennsylvania
Department of Molecular Design
and Diversity (J.R.T., K.C.)
Merck Research Laboratories,
Rahway, New Jersey

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.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 2001 by the American Society for Pharmacology and Experimental Therapeutics.