Stereoselective hydroxylation of nonpeptidic HIV protease inhibitors by CYP2D6.

Autor: Zhao Z; Drug Metabolism Research, Pharmacia & Upjohn, Inc., Kalamazoo, Michigan, USA. zhiyang_zhao@groton.pfizer.com, Koeplinger KA, Waldon DJ
Jazyk: angličtina
Zdroj: Chirality [Chirality] 1999; Vol. 11 (9), pp. 731-9.
DOI: 10.1002/(SICI)1520-636X(1999)11:9<731::AID-CHIR9>3.0.CO;2-3
Abstrakt: PNU-106893, N-{3-[1-(4-hydroxy-2-oxo-6-phenyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl)-2, 2-dimethylpropyl]phenyl}-1-methyl-1H-imidazole-4-sulfonamide, is a selective HIV aspartyl protease inhibitor under evaluation as a potential oral treatment of acquired immunodeficiency disease. PNU-106893 is a mixture of four stereoisomers, designated PNU-109165 (3alphaR, 6S), PNU-109166 (3alphaR, 6R), PNU-109167 (3alphaS, 6S), and PNU-109168 (3alphaS, 6R). The major P450 isoforms involved in the metabolism of PNU-106893 and its pure stereoisomers are identified as CYP2D6 and CYP3A4. The major oxidative biotransformation pathway of PNU-106893 which occurs in microsomal incubations appears to be hydroxylation of the phenylethyl side chain attached to the C-6 carbon of the dihydropyrone ring. This hydroxylation is mediated by CYP2D6 only and the process is stereoselective for the 6R absolute stereochemistry. The configuration at position 3 appears to play a minor role in the CYP2D6 mediated hydroxylation. These insights have impacted drug candidate selection for this class of compounds.
(Copyright 1999 Wiley-Liss, Inc.)
Databáze: MEDLINE
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