Oxidative metabolism of the trifluoromethoxy moiety of OSI-930.
Cytochrome P450 can catalyze a wide array of remarkable oxidations, including O-dealkylations, which are performed via oxidation of the alpha-carbon of the ether. When C-H bonds are replaced with C-F bonds, however, the bond strength is much greater, and it significantly deters oxidation at the carbon. Another recently elucidated reaction catalyzed by P450, ipso substitution, results in displacement of aromatic ring substituents such as an alkoxy group via hydroxyl substitution. Through LC/MS/MS, we show the CYP-mediated oxidative displacement of the trifluoromethoxy group from the phenyl constituent in OSI-930, a novel small molecule c-Kit/VEGF-r inhibitor in clinical studies to treat cancer. Based on C-F bond strength, reported phenacetin studies, and alpha-quaternary alkylphenol studies, we propose an ipso-substitution mechanism for this oxidative biotransformation. In vivo, this hydroxylated metabolite goes on to form the ether conjugate with glucuronide.
Dihel
Larry
L
Drug Metabolism and Pharmacokinetics, OSI Pharmaceuticals, Inc., Boulder, CO 80301, USA.
Kittleson
Christine
C
Mulvihill
Kristen
K
Johnson
William W
WW
D000818:Animals; D001711:Biotransformation; D002853:Chromatography, Liquid / Q000379:methods; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D011804:Quinolines / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D053719:Tandem Mass Spectrometry / Q000379:methods; D013876:Thiophenes / Q000737:chemistry / Q000493:pharmacokinetics*
C505207:OSI 930; D011804:Quinolines; D013876:Thiophenes; D003577:Cytochrome P-450 Enzyme System