title: 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).
abstract: Various 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.
authors.affiliation: Drug Discovery Department, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Risch
authors.affiliation: Drug Discovery Department, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pfeifer
authors.affiliation: Drug Discovery Department, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Jerome
authors.initials: J
authors.lastname: Segrestaa
authors.affiliation: Drug Discovery Department, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Heinz
authors.initials: H
authors.lastname: Fretz
authors.affiliation: Drug Discovery Department, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Julien
authors.initials: J
authors.lastname: Pothier
mesh_terms: D001711:Biotransformation; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000378:metabolism* / Q000652:urine; D053858:Metabolic Networks and Pathways; D008862:Microsomes, Liver / Q000378:metabolism; D009281:Naphthalenes / Q000378:metabolism* / Q000652:urine; D010084:Oxidation-Reduction; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism
chemical_list: C583159:2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido(4,3-b)indol-5(2H)-yl)acetic acid; D007211:Indoles; D009281:Naphthalenes; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C036293:prostaglandin D2 receptor