title: 2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists: structure activity relationships of the 2-oxy pyridine C-region.
abstract: The structure activity relationships of 2-oxy pyridine derivatives in the C-region of N-(6-trifluoromethyl-pyridin-3-ylmethyl) 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as hTRPV1 antagonists were investigated. The analysis indicated that the lipophilicity of the 2-oxy substituents was critical for potent antagonism and 4 or 5 carbons appeared to be optimal for activity. Multiple compounds proved to have comparable activity to 1, which had been reported as the most potent antagonist for capsaicin activity among the previous series of compounds. Further analysis of compounds 22 (2-isobutyloxy) and 53 (2-benzyloxy) in the formalin test in mice demonstrated strong analgesic activity with full efficacy. Docking analysis of 53S using our hTRPV1 homology model indicated that the A- and B-region 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamide made important hydrophobic and hydrogen bonding interactions with Tyr511 and that the C-region 6-trifluoromethyl and 2-benzyloxy groups of pyridine occupied the two hydrophobic binding pockets, respectively.
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: Shivaji A
authors.initials: SA
authors.lastname: Thorat
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Kang
authors.forename: HyungChul
authors.initials: H
authors.lastname: Ryu
authors.forename: Myeong Seop
authors.initials: MS
authors.lastname: Kim
authors.forename: Ho Shin
authors.initials: HS
authors.lastname: Kim
authors.forename: Jihyae
authors.initials: J
authors.lastname: Ann
authors.forename: Taehwan
authors.initials: T
authors.lastname: Ha
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Kim
authors.forename: Karam
authors.initials: K
authors.lastname: Son
authors.forename: Sun
authors.initials: S
authors.lastname: Choi
authors.forename: Peter M
authors.initials: PM
authors.lastname: Blumberg
authors.forename: Robert
authors.initials: R
authors.lastname: Frank
authors.forename: Gregor
authors.initials: G
authors.lastname: Bahrenberg
authors.forename: Klaus
authors.initials: K
authors.lastname: Schiene
authors.forename: Thomas
authors.initials: T
authors.lastname: Christoph
authors.forename: Jeewoo
authors.initials: J
authors.lastname: Lee
mesh_terms: D044482:Benzeneacetamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*
chemical_list: D044482:Benzeneacetamides; D011725:Pyridines; D013449:Sulfonamides; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human