title: Identification of a novel 2-pyridyl-benzensulfonamide derivative, RQ-00203078, as a selective and orally active TRPM8 antagonist.
abstract: A novel series of 2-pyridyl-benzensulfonamide derivatives have been identified as selective and orally active TRPM8 antagonists via high throughput screening (HTS). Exploration of the structure-activity relationships of compound 1 has led to the identification of RQ-00203078 (compound 36) as a highly selective, potent and orally available TRPM8 antagonist. RQ-00203078 demonstrated excellent in vivo activity in a dose dependent manner with an ED50 value of 0.65 mg/kg in the icilin-induced wet-dog shakes model in rats after oral administration and may become an important pharmacological tool for fully assessing the potential therapeutic use of the targets activated by cold stimulation.
authors.affiliation: Research and Development, RaQualia Pharma Inc., 5-2 Taketoyo, Aichi 470-2341, Japan. Electronic address: masashi.ohmi@raqualia.com.
authors.forename: Masashi
authors.initials: M
authors.lastname: Ohmi
authors.affiliation: Research and Development, RaQualia Pharma Inc., 5-2 Taketoyo, Aichi 470-2341, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shishido
authors.affiliation: Research and Development, RaQualia Pharma Inc., 5-2 Taketoyo, Aichi 470-2341, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Research and Development, RaQualia Pharma Inc., 5-2 Taketoyo, Aichi 470-2341, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ando
authors.affiliation: Research and Development, RaQualia Pharma Inc., 5-2 Taketoyo, Aichi 470-2341, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Fujiuchi
authors.affiliation: Research and Development, RaQualia Pharma Inc., 5-2 Taketoyo, Aichi 470-2341, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Yamada
authors.affiliation: Research and Development, RaQualia Pharma Inc., 5-2 Taketoyo, Aichi 470-2341, Japan.
authors.forename: Shuzo
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Research and Development, RaQualia Pharma Inc., 5-2 Taketoyo, Aichi 470-2341, Japan. Electronic address: kiyoshi.kawamura@raqualia.com.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kawamura
mesh_terms: D000818:Animals; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D050053:TRPM Cation Channels
keywords: Cold allodynia; RQ-00203078; Sulfonamide; TRPM8 antagonist; Wet-dog shakes