Ezlopitant

Investigation of the metabolism of ezlopitant alkene (CJ-12,458), an active metabolite 93... 

Obach RS. Mechanism of cytochrome P4503A4- and 2D6-catalyzed dehydrogenation of ezlopitant as probed with isotope effects using five deuterated analogs. Drug Metab Dispos 2001 29(12) 1599-1607. 

Kamel AM, Zandi KS, Massefski WW. 2003. Identification of the degradation product of ezlopitant, a non-peptidic substance P antagonist receptor, by hydrogen deuterium exchange, electrospray ionization tandem mass spectrometry (ESI/MS/MM) and nuclear magnetic resonance (NMR) spectroscopy. J Pharm Biomed Anal 31 1211. 

The isopropyl group of ezlopitant, which bears a 2-methoxy-5-isopropylbenzylamino group, is oxidized by both CYP3A4 and CYP2D6 to the tertiary alcohol and the desaturated 1-methylvinyl moiety . The alcohol was specifically shown not to be a precursor of the unsaturated product, and a small primary isotope effect was observed when deuterium was placed at the benzylic but not methyl carbons of the isopropyl group. Although not studied in detail, concurrent hydroxylation and... 

Obach RS. Metabolism of ezlopitant, a nonpeptidic substance P receptor antagonist, in liver microsomes enzyme kinetics, cytochrome P450 isoform identity, and in vitro-in vivo correlation. Drug Metab Dispos 2000 28 1069 1076. 

Carbon oxidation reactions nsnally result in the formation of alcohol products, but in some instances they produce desaturated metabolites. Early examples are provided by the P450-cata-lyzed oxidative A -desaturation of valproic acid [88,89], A -desaturation of testosterone [90], and A -desaturation of sterols [91, 92] (Fig. 4.11). Additional examples are provided by the desaturation of lovastatin [93], ezlopitant [94], and capsaicin [95] (Fig. 4.12). In all these examples, hydroxylation to give the normally expected alcohol product also is observed, which suggests that in these substrates desaturation diverges at some point from the normal substrate hydroxylation reaction. 

Fig. 4.12 Cytochrome P450-catalyzed desaturation of the drags lovastatin (a), and ezlopitant (b), and of the natural product capsaicin (c)...

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