title: 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 (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.
authors.affiliation: Drug Metabolism Research, Pharmacia & Upjohn, Inc., Kalamazoo, Michigan, USA. zhiyang_zhao@groton.pfizer.com
authors.forename: Z
authors.initials: Z
authors.lastname: Zhao
authors.forename: K A
authors.initials: KA
authors.lastname: Koeplinger
authors.forename: D J
authors.initials: DJ
authors.lastname: Waldon
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017320:HIV Protease Inhibitors / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D007093:Imidazoles / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D011714:Pyrans / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D019380:Anti-HIV Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D007093:Imidazoles; C401903:PNU 106893; D011714:Pyrans; D011994:Recombinant Proteins; D019389:Cytochrome P-450 CYP2D6