title: Discovery of aminobenzyloxyarylamides as κ opioid receptor selective antagonists: application to preclinical development of a κ opioid receptor antagonist receptor occupancy tracer.
abstract: Arylphenylpyrrolidinylmethylphenoxybenzamides were found to have high affinity and selectivity for κ opioid receptors. On the basis of receptor binding assays in Chinese hamster ovary (CHO) cells expressing cloned human opioid receptors, (S)-3-fluoro-4-(4-((2-(3-fluorophenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide (25) had a K(i) = 0.565 nM for κ opioid receptor binding while having a K(i) = 35.8 nM for μ opioid receptors and a K(i) = 211 nM for δ opioid receptor binding. Compound 25 was also a potent antagonist of κ opioid receptors when tested in vitro using a [(35)S]-guanosine 5'O-[3-thiotriphosphate] ([(35)S]GTP-γ-S) functional assay in CHO cells expressing cloned human opioid receptors. Compounds were also evaluated for potential use as receptor occupancy tracers. Tracer evaluation was done in vivo, using liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods, precluding the need for radiolabeling. (S)-3-Chloro-4-(4-((2-(pyridine-3-yl)pyrrolidin-1-yl)methyl)phenoxy)benzamide (18) was found to have favorable properties for a tracer for receptor occupancy, including good specific versus nonspecific binding and good brain uptake.
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana 46285-0150, United States. mitch@lilly.com
authors.forename: Charles H
authors.initials: CH
authors.lastname: Mitch
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Quimby
authors.forename: Nuria
authors.initials: N
authors.lastname: Diaz
authors.forename: Concepcion
authors.initials: C
authors.lastname: Pedregal
authors.forename: Marta G
authors.initials: MG
authors.lastname: de la Torre
authors.forename: Alma
authors.initials: A
authors.lastname: Jimenez
authors.forename: Qing
authors.initials: Q
authors.lastname: Shi
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Canada
authors.forename: Steven D
authors.initials: SD
authors.lastname: Kahl
authors.forename: Michael A
authors.initials: MA
authors.lastname: Statnick
authors.forename: David L
authors.initials: DL
authors.lastname: McKinzie
authors.forename: Dana R
authors.initials: DR
authors.lastname: Benesh
authors.forename: Karen S
authors.initials: KS
authors.lastname: Rash
authors.forename: Vanessa N
authors.initials: VN
authors.lastname: Barth
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D002853:Chromatography, Liquid; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D053719:Tandem Mass Spectrometry
chemical_list: C570402:3-chloro-4-(4-((2-(3-pyridyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide; C570403:3-fluoro-4-(4-((2-(3-fluorophenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide; D001549:Benzamides; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa