Mechanism-based inhibitors of prostaglandin omega-hydroxylase: (R)- and (S)-12-hydroxy-16-heptadecynoic acid and 2,2-dimethyl-12-hydroxy-16-heptadecynoic acid.
12-Hydroxy-16-heptadecynoic acid has been shown to selectively inactivate cytochrome P450 4A4, a pulmonary cytochrome P450 enzyme that catalyzes the omega-hydroxylation of prostaglandins [Muerhoff, A. S.; Williams, D. E.; Reich, N. O.; CaJacob, C. A.; Ortiz de Montellano, P. R.; Masters, B. S. S. J. Biol. Chem. 1989, 264, 749-756]. Potent, specific inhibitors of this enzyme are required to explore its physiological role. In a continuing effort to develop such agents, the two enantiomers of 12-hydroxy-16-heptadecynoic acid have been stereospecifically synthesized, their absolute stereochemistry confirmed, and the dependence of enzyme inactivation on absolute stereochemistry determined using cytochrome P450 4A4 purified from the lungs of pregnant rabbits. The 12S enantiomer is roughly twice as active (KI = 1.8 microM, t1/2 = 0.7 min) as the 12R enantiomer (KI = 3.6 microM, t1/2 = 0.8 min), but the chirality of the hydroxyl group is not a major determinant of the specificity for the prostaglandin omega-hydroxylase. The flexibility of the acyclic skeleton of the inhibitor may account for the relatively low enantiomeric discrimination. 2,2-Dimethyl-12-hydroxy-16-heptadecynoic acid, an analogue that cannot undergo beta-oxidation, has also been synthesized as a potential in vivo inhibitor of the enzyme and has been shown to inactivate the purified enzyme with KI = 4.9 microM and t1/2 = 1.0 min. These acetylenic agents, particularly the dimethyl analog, are promising in vivo inhibitors of cytochrome P450 4A4.
Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco 94143-0446.
A
A
Burger
J E
JE
Clark
M
M
Nishimoto
A S
AS
Muerhoff
B S
BS
Masters
P R
PR
Ortiz de Montellano
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D005229:Fatty Acids, Monounsaturated / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D011247:Pregnancy; D011817:Rabbits; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D065607:Cytochrome P-450 Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; C068165:12-hydroxy-16-heptadecynoic acid; C081282:2,2-dimethyl-12-hydroxy-16-heptadecynoic acid; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C026961:prostaglandin omega hydroxylases