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PROTEIN COVALENT BINDING OF MAXIPOST THROUGH A CYTOCHROME P450-MEDIATED ORTHO-QUINONE METHIDE INTERMEDIATE IN RATS

Preclinical Candidate Optimization (D.Z., V.R., R.D., M.Z., L.K., J.M.), Discovery Chemistry (M.O., J.K.R.), Analytical Research and Development, Pharmaceutical Research Institute (R.G.), Bristol-Myers Squibb, Princeton, New Jersey

(3S)-(+)-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one) (MaxiPost, BMS-204352) is a potent and specific opener for maxi-K channels and has potential to prevent and treat ischemic stroke. Following single intravenous doses of [¹⁴C]BMS-204352 to rats, only 10 to 12% of radioactivity was extractable from plasma with organic solvents. The unextractable radioactivity remained associated with the proteins (mostly albumin) after SDS-polyacrylamide gel eletrophoresis or dialysis. Following acid hydrolysis in 6 M HCl for 24 h at 110°C from plasma proteins collected from nine rats dosed with [¹⁴C]BMS-204352, one major radioactive product was isolated and identified as a lysine-adduct of des-fluoro des-O-methyl BMS-204352 by liquid chromatography/mass spectrometry and NMR analyses as well as by comparison with the synthetic analog, lysine-adduct of des-fluoro BMS-204352 (BMS-349821). The covalent binding of BMS-204352 results from the displacement of the ring-fluorine atom of des-O-methyl BMS-204352 with the -amino group of a lysine residue. Microsomal incubations of [¹⁴C]BMS-204352 resulted in low levels of covalent binding of radioactivity to proteins. This in vitro covalent binding required cytochrome P450-reductase cofactor NADPH and was attenuated by glutathione. P4503A inhibitors ketoconazole and troleadomycin selectively prevented the covalent binding in vitro. Based on these observations, a two-step bioactivation process for the protein covalent binding of BMS-204352 was postulated: 1) P4503A-mediated O-demethylation leading to spontaneous release of HF and the formation of an ortho-quinone methide reactive metabolite and 2) nucleophilic addition of the -amino group of protein lysine residue(s) in protein to form des-fluoro des-O-methyl BMS-204352 lysine adduct.

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