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‑1<i>H</i>‑pyrido[4,3‑<i>b</i>]indol-5(2<i>H</i>)‑yl)acetic Acid (Setipiprant/ACT-129968) Philippe Risch Thomas Pfeifer Jerome Segrestaa Heinz Fretz Julien Pothier 10.1021/acs.jmedchem.5b00824.s002 https://acs.figshare.com/articles/dataset/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_1_i_H_i_pyrido_4_3_i_b_i_indol_5_2_i_H_i_yl_acetic_Acid/2558572 Various racemic and enantioenriched (<i>trans</i>)-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-1<i>H</i>-pyrido­[4,3-<i>b</i>]­indol-5­(2<i>H</i>)-yl)­acetic acid (<b>1</b>, Setipiprant/ACT-129968) were synthesized in order to gain insight into regio- and enantioselectivity of the metabolic oxidation of <b>1</b> 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-((<i>trans</i>)-3,4-dihydroxy-3,4-dihydronaphthalene-1-carbonyl)– and 2-(2-((<i>trans</i>)-5,6-dihydroxy-5,6-dihydronaphthalene-1-carbonyl)-8-fluoro-3,4-dihydro-1<i>H</i>-pyrido­[4,3-<i>b</i>]­indol-5­(2<i>H</i>)-yl)­acetic acid, respectively, each composed of two enantiomers with 68% and 44% ee in favor of (+)-(3<i>S</i>,4<i>S</i>)-M7 and (+)-(5<i>S</i>,6<i>S</i>)-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-5<i>H</i>-pyrido­[4,3-<i>b</i>]­indol-5-yl)­acetic acid, respectively. 2015-10-22 00:00:00 fluoro Major Metabolic Oxidation Path analogue Setipiprant tran CRTh Th 2 Cells Naphthoyl Group ADME study M 13 gain insight Analytical data M 9 metabolites M 3 metabolites M 7 acid