Pyridine C-region analogs of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists

• Published in: European journal of medicinal chemistry Vol. 93; pp. 101 - 108
• Main Authors: Ryu, HyungChul, Seo, Sejin, Lee, Jee-Young, Ha, Tae-Hwan, Lee, Sunho, Jung, Aeran, Ann, Jihyae, Kim, Sung-Eun, Yoon, Suyoung, Hong, Mannkyu, Blumberg, Peter M., Frank-Foltyn, Robert, Bahrenberg, Gregor, Schiene, Klaus, Stockhausen, Hannelore, Christoph, Thomas, Frormann, Sven, Lee, Jeewoo
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 26.03.2015; Elsevier
• Subjects: Analgesic; Analgesics - chemical synthesis; Analgesics - chemistry; Analgesics - pharmacology; Analgesics - therapeutic use; Animals; Benzeneacetamides - chemical synthesis; Benzeneacetamides - chemistry; Benzeneacetamides - pharmacology; Benzeneacetamides - therapeutic use; Chemistry, Medicinal; Life Sciences & Biomedicine; Mice; Molecular Structure; Pain - drug therapy; Pain Measurement; Pharmacology & Pharmacy; Pyridines - chemistry; Science & Technology; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; TRPV Cation Channels - antagonists & inhibitors; TRPV1 antagonists; Vanilloid receptor 1; Vanilloid receptor 1; TRPV1 antagonists; Analgesic; VANILLOID CAPSAICIN RECEPTORS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.02.001

A series of pyridine derivatives in the C-region of N-((6-trifluoromethyl-pyridin-3-yl)methyl) 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. The SAR analysis indicated that 6-difluorochloromethyl pyridine derivatives were the best surrogates of the C-region for previous leads. Among them, compound 31 showed excellent antagonism to capsaicin as well as to multiple hTRPV1 activators. It demonstrated strong analgesic activity in the formalin test in mice with full efficacy and it blocked capsaicin-induced hypothermia in vivo. [Display omitted] •A series of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists.•Compound 31 showed potent antagonisms toward hTRPV1 multiple activators.•Compound 31 exhibited strong analgesic activity.