title: 2-Alkyl/alkenyl substituted pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as highly potent TRPV1 antagonists.
abstract: A series of 2-alkyl/alkenyl pyridine C-region derivatives of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Multiple compounds showed excellent and stereospecific TRPV1 antagonism with better potency than previous lead 2. Among them, compound 15f demonstrated a strong analgesic profile in a rat neuropathic pain model and blocked capsaicin-induced hypothermia in a dose-dependent manner. Docking analysis of (S)-15f with our hTRPV1 homology model provided insight into its specific binding mode.
authors.affiliation: Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: HyungChul
authors.initials: H
authors.lastname: Ryu
authors.affiliation: Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Sejin
authors.initials: S
authors.lastname: Seo
authors.affiliation: Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Seong-Hee
authors.initials: SH
authors.lastname: Cho
authors.affiliation: Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Ho Shin
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Laboratory of Medicinal Chemistry, 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: Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea; Department of Pharmaceutical Science and Technology, College of Health and Medical Science, Catholic University of Deagu, Gyeongsan-si, Gyeongsangbuk-do 712-702, Republic of Korea.
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Kang
authors.affiliation: National Leading Research Lab of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Karam
authors.initials: K
authors.lastname: Son
authors.affiliation: National Leading Research Lab of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Minghua
authors.initials: M
authors.lastname: Cui
authors.affiliation: National Leading Research Lab of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Sun-hye
authors.initials: SH
authors.lastname: Hong
authors.affiliation: National Leading Research Lab of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Pankaz Kumar
authors.initials: PK
authors.lastname: Sharma
authors.affiliation: National Leading Research Lab of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, 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: 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: Hannelore
authors.initials: H
authors.lastname: Stockhausen
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: 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: Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: jeewoo@snu.ac.kr.
authors.forename: Jeewoo
authors.initials: J
authors.lastname: Lee
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010666:Phenylpropionates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*
chemical_list: D006845:Hydrocarbons, Fluorinated; D010666:Phenylpropionates; D011725:Pyridines; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C023666:pyridine
keywords: Capsaicin; Molecular modeling; Resiniferatoxin; TRPV1 antagonist; Vanilloid receptor 1