Verification of the Major Metabolic Oxidation Path for the Naphthoyl Group in Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells (CRTh2) Antagonist 2-(2-(1-Naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic Acid (Setipiprant/ACT-129968)
October 2015
in “Journal of Medicinal Chemistry”
TLDR The document confirms the structures of major metabolites of the CRTh2 antagonist Setipiprant and identifies minor metabolites.
The document from 2015 investigated the metabolic oxidation of the CRTh2 antagonist 2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (Setipiprant/ACT-129968). Various analogues of this compound were synthesized to understand the regio- and enantioselectivity of its metabolic oxidation and to confirm the structures of four metabolites proposed in a previous clinical ADME study. The two major metabolites, M7 and M9, were confirmed as specific dihydroxy-dihydronaphthalene-carbonyl compounds, each composed of two enantiomers with 68% and 44% enantiomeric excess in favor of (+)-(3S,4S)-M7 and (+)-(5S,6S)-M9, respectively. The minor metabolites M3 and M13 were identified as specific hydroxy-naphthoyl compounds.
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