jm5b00824_si_002.csv (0.48 kB)
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)
dataset
posted on 2015-10-22, 00:00 authored by Philippe Risch, Thomas Pfeifer, Jerome Segrestaa, Heinz Fretz, Julien PothierVarious racemic and enantioenriched
(trans)-X,Y-dihydroxy-X,Y-dihydronaphthoyl
analogues as well as X-hydroxy-naphthoyl analogues of CRTh2 antagonist
2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (1, Setipiprant/ACT-129968) were synthesized in order to gain insight
into regio- and enantioselectivity of the metabolic oxidation of 1 and to verify the structures of four metabolites that were
proposed earlier in a clinical ADME study. Analytical data of the
synthetic standards were compared with data from samples of biological
origin. The two major metabolites M7 and M9 were unambiguously verified
as 2-(2-((trans)-3,4-dihydroxy-3,4-dihydronaphthalene-1-carbonyl)–
and 2-(2-((trans)-5,6-dihydroxy-5,6-dihydronaphthalene-1-carbonyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid, respectively, each composed of two enantiomers
with 68% and 44% ee in favor of (+)-(3S,4S)-M7 and (+)-(5S,6S)-M9,
respectively. Likewise, minor metabolites M3 and M13 were identified
as 2-(8-fluoro-2-(5-hydroxy-1-naphthoyl)– and 2-(8-fluoro-2-(4-hydroxy-1-naphthoyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5-yl)acetic acid,
respectively.