title: 6,6-Fused heterocyclic ureas as highly potent TRPV1 antagonists.
abstract: A series of N-[{2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)-pyridin-3-yl}methyl] N'-(6,6-fused heterocyclic) ureas have been investigated as hTRPV1 antagonists. Among them, compound 15 showed highly potent TRPV1 antagonism to capsaicin, with Ki(ant)=0.2nM, as well as antagonism to other activators, and it was efficacious in a pain model. A docking study of 15 with our hTRPV1 homology model indicates that there is crucial hydrogen bonding between the ring nitrogen and the receptor, contributing to its potency.
authors.affiliation: Shenyang Pharmaceutical University, Shenyang 110016, China; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Hyo-Shin
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Sunho
authors.initials: S
authors.lastname: Lee
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Aeran
authors.initials: A
authors.lastname: Jung
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Kim
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Jihyae
authors.initials: J
authors.lastname: Ann
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Suyoung
authors.initials: S
authors.lastname: Yoon
authors.affiliation: National Leading Research Laboratory of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Science and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Sun
authors.initials: S
authors.lastname: Choi
authors.affiliation: National Leading Research Laboratory of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Science and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Blumberg
authors.affiliation: Grunenthal Innovation, Grunenthal GmbH, D-52078 Aachen, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Frank-Foltyn
authors.affiliation: Grunenthal Innovation, Grunenthal GmbH, D-52078 Aachen, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Bahrenberg
authors.affiliation: Grunenthal Innovation, Grunenthal GmbH, D-52078 Aachen, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schiene
authors.affiliation: Grunenthal Innovation, Grunenthal GmbH, D-52078 Aachen, Germany.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Stockhausen
authors.affiliation: Grunenthal Innovation, Grunenthal GmbH, D-52078 Aachen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Christoph
authors.affiliation: Grunenthal Innovation, Grunenthal GmbH, D-52078 Aachen, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Frormann
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Jeewoo
authors.initials: J
authors.lastname: Lee
mesh_terms: D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D007546:Isoquinolines; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D014508:Urea
keywords: Analgesic; Molecular modeling; TRPV1 antagonist; Vanilloid receptor 1