title: Structure activity relationships of benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists.
abstract: A series of 2-substituted 4-(trifluoromethyl)benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis indicated that the phenyl C-region derivatives exhibited better antagonism than those of the corresponding pyridine surrogates for most of the series examined. Among the phenyl C-region derivatives, the two best compounds 43 and 44S antagonized capsaicin selectively relative to their antagonism of other activators and showed excellent potencies with K(i(CAP))=0.3 nM. These two compounds blocked capsaicin-induced hypothermia, consistent with TRPV1 as their site of action, and they demonstrated promising analgesic activities in a neuropathic pain model without hyperthermia. The docking study of 44S in our hTRPV1 homology model indicated that its binding mode was similar with that of its pyridine surrogate in the A- and B-regions but displayed a flipped configuration in the C-region.
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: Jihyae
authors.initials: J
authors.lastname: Ann
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.
authors.forename: Mi-Yeon
authors.initials: MY
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: Hyuk-Min
authors.initials: HM
authors.lastname: Kim
authors.affiliation: J2H Biotech, Ansan-si, Gyeonggi-do, Republic of Korea.
authors.forename: HyungChul
authors.initials: H
authors.lastname: Ryu
authors.affiliation: J2H Biotech, Ansan-si, Gyeonggi-do, Republic of Korea.
authors.forename: Sunjoo
authors.initials: S
authors.lastname: Kim
authors.affiliation: 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 Laboratory 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: Sunhye
authors.initials: S
authors.lastname: Hong
authors.affiliation: National Leading Research Laboratory 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 Laboratory 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: Grünenthal Innovation, Grünenthal GmbH, D-52078 Aachen, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Frank-Foltyn
authors.affiliation: Grünenthal Innovation, Grünenthal GmbH, D-52078 Aachen, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Bahrenberg
authors.affiliation: Grünenthal Innovation, Grünenthal GmbH, D-52078 Aachen, Germany.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Stockhausen
authors.affiliation: Grünenthal Innovation, Grünenthal GmbH, D-52078 Aachen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Christoph
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: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry*; D000818:Animals; D001665:Binding Sites; D002211:Capsaicin / Q000633:toxicity; D006801:Humans; D007035:Hypothermia / Q000139:chemically induced / Q000188:drug therapy; D051379:Mice; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000577:Amides; D000700:Analgesics; D050916:TRPV Cation Channels; D002211:Capsaicin
keywords: Analgesic; TRPV1 antagonists; Vanilloid receptor 1