Stereoselective hydroxylation of nonpeptidic HIV protease inhibitors by CYP2D6

Abstract

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 (3αR, 6S), PNU‐109166 (3αR, 6R), PNU‐109167 (3αS, 6S), and PNU‐109168 (3αS, 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. Chirality 11:731–739, 1999. © 1999 Wiley‐Liss, Inc.