Identification of a novel 2-pyridyl-benzensulfonamide derivative, RQ-00203078, as a selective and orally active TRPM8 antagonist

  • Bioorg Med Chem Lett. 2014 Dec 1;24(23):5364-8. doi: 10.1016/j.bmcl.2014.10.074.
Masashi Ohmi  1 ,  Yuji Shishido  2 ,  Tadashi Inoue  2 ,  Kazuo Ando  2 ,  Akiyoshi Fujiuchi  2 ,  Akiko Yamada  2 ,  Shuzo Watanabe  2 ,  Kiyoshi Kawamura  3
Affiliations
  • 1. Research and Development, RaQualia Pharma Inc., 5-2 Taketoyo, Aichi 470-2341, Japan. Electronic address: [email protected].
  • 2. Research and Development, RaQualia Pharma Inc., 5-2 Taketoyo, Aichi 470-2341, Japan.
  • 3. Research and Development, RaQualia Pharma Inc., 5-2 Taketoyo, Aichi 470-2341, Japan. Electronic address: [email protected].
PMID: 25455182 DOI: 10.1016/j.bmcl.2014.10.074
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.

Keywords
Cold allodynia; RQ-00203078; Sulfonamide; TRPM8 antagonist; Wet-dog shakes.
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