title: 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent transient receptor potential vanilloid 1 (TRPV1) antagonists: structure-activity relationships of 2-amino derivatives in the N-(6-trifluoromethylpyridin-3-ylmethyl) C-region.
abstract: A series of N-(2-amino-6-trifluoromethylpyridin-3-ylmethyl)-2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were designed combining previously identified pharmacophoric elements and evaluated as hTRPV1 antagonists. The SAR analysis indicated that specific hydrophobic interactions of the 2-amino substituents in the C-region of the ligand were critical for high hTRPV1 binding potency. In particular, compound 49S was an excellent TRPV1 antagonist (K(i(CAP)) = 0.2 nM; IC(50(pH)) = 6.3 nM) and was thus approximately 100- and 20-fold more potent, respectively, than the parent compounds 2 and 3 for capsaicin antagonism. Furthermore, it demonstrated strong analgesic activity in the rat neuropathic model superior to 2 with almost no side effects. Compound 49S antagonized capsaicin induced hypothermia in mice but showed TRPV1-related hyperthermia. The basis for the high potency of 49S compared to 2 is suggested by docking analysis with our hTRPV1 homology model in which the 4-methylpiperidinyl group in the C-region of 49S made additional hydrophobic interactions with the hydrophobic region.
authors.affiliation: Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Myeong Seop
authors.initials: MS
authors.lastname: Kim
authors.forename: HyungChul
authors.initials: H
authors.lastname: Ryu
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Kang
authors.forename: Seong-Hee
authors.initials: SH
authors.lastname: Cho
authors.forename: Sejin
authors.initials: S
authors.lastname: Seo
authors.forename: Young Soo
authors.initials: YS
authors.lastname: Park
authors.forename: Mi-Yeon
authors.initials: MY
authors.lastname: Kim
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Kwak
authors.forename: Yong Soo
authors.initials: YS
authors.lastname: Kim
authors.forename: Rahul S
authors.initials: RS
authors.lastname: Bhondwe
authors.forename: Ho Shin
authors.initials: HS
authors.lastname: Kim
authors.forename: Seul-gi
authors.initials: SG
authors.lastname: Park
authors.forename: Karam
authors.initials: K
authors.lastname: Son
authors.forename: Sun
authors.initials: S
authors.lastname: Choi
authors.forename: Ian A
authors.initials: IA
authors.lastname: DeAndrea-Lazarus
authors.forename: Larry V
authors.initials: LV
authors.lastname: Pearce
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: Hannelore
authors.initials: H
authors.lastname: Stockhausen
authors.forename: Babette Y
authors.initials: BY
authors.lastname: Kögel
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: D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D016466:CHO Cells; D002211:Capsaicin / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004298:Dopamine / Q000031:analogs & derivatives / Q000494:pharmacology; D006358:Hot Temperature; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D062105:Molecular Docking Simulation; D009437:Neuralgia / Q000188:drug therapy; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: C577116:2-(3-fluoro-4-(methylsulfonamido)phenyl)-N-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide; D000700:Analgesics; D011725:Pyridines; D013449:Sulfonamides; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C006374:N-acetyldopamine; D002211:Capsaicin; D004298:Dopamine