Stereoselective hydroxylation of nonpeptidic HIV protease inhibitors by CYP2D6

✍ Scribed by Zhiyang Zhao; Kenneth A. Koeplinger; Daniel J. Waldon

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 251 KB
• Volume: 11
• Category: Article
• ISSN: 0899-0042
• DOI: 10.1002/(sici)1520-636x(1999)11:9<731::aid-chir9>3.0.co;2-3

✦ Synopsis

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 (3␣R, 6S), PNU-109166 (3␣R, 6R), PNU-109167 (3␣S, 6S), and PNU-109168 (3␣S, 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.