Number, nature as well as the concentration of metabolites appearing in the blood and organs after administering a drug candidate to a living creature may significantly affect drug development. As a result, early identification of metabolites has become of utmost importance in drug discovery and development.Two major metabolites M7  and M9  were detected by LC-MS/MS after incubating 14C labeled CRTh2 antagonist 1  with human hepatocytes. Analysis of the mass spectra (MS/MS) indicated that the tetrahydropyridoindole core of 1  remained intact whereas its naphthyl ring seemed to be converted to two distinct dihydroxy-dihydronaphthalene regioisomers as shown with 2 . Based on literature precedence, conversion of 1  to M7  and M9  in two consecutive enzymatic steps was assumed: an initial cytochrome P450 catalyzed epoxidation of the naphthyl ring is followed by an epoxide hydrolase catalyzed epoxide ring opening to form two distinct vicinal trans-dihydroxy-dihydronaphthalene regioisomers. Consequently, the four most plausible regioisomers 2a-d  were synthesized in racemic and enantioenriched form. Structure and absolute stereochemistry of the two metabolites M7  and M9  could unequivocally be assigned by comparing analytical and spectral data of the synthetic with the biological samples.

Structure elucidation of two major metabolites of CRTh2 antagonist 2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (ACT-129968, setipiprant)

246th National Meeting (2013)

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