Pharmacological evaluation of novel (6-aminopyridin-3-yl)(4-(pyridin-2-yl)piperazin-1-yl) methanone derivatives as TRPV4 antagonists for the treatment of pain

Bioorg Med Chem. 2017 Apr 1;25(7):2177-2190. doi: 10.1016/j.bmc.2017.02.047. Epub 2017 Mar 1.

Abstract

A novel series of (6-aminopyridin-3-yl)(4-(pyridin-2-yl)piperazin-1-yl) methanone derivatives were identified as selective transient receptor potential vanilloid 4 (TRPV4) channel antagonist and showed analgesic effect in Freund's Complete Adjuvant (FCA) induced mechanical hyperalgesia model in guinea pig and rat. Modification of right part based on the compound 16d which was disclosed in our previous communication led to the identification of compound 26i as a flagship compound. In this paper, we described the details about design, synthesis and structure-activity relationship (SAR) analysis at right and left part of these derivatives (Fig. 1).

Keywords: Ion channel; Pain; TRPV4 antagonist; Transient receptor potential vanilloid 4; Vanilloid receptor.

MeSH terms

  • Analgesics / chemistry
  • Analgesics / pharmacology*
  • Animals
  • Azabicyclo Compounds / chemistry
  • Azabicyclo Compounds / pharmacology*
  • Guinea Pigs
  • Humans
  • Microsomes / drug effects
  • Pain Management / methods*
  • Proton Magnetic Resonance Spectroscopy
  • Rats
  • Spectrometry, Mass, Electrospray Ionization
  • Structure-Activity Relationship
  • TRPV Cation Channels / antagonists & inhibitors*
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*

Substances

  • (6-((2',4'-dimethyl-(4,5'-bithiazol)-2-yl)amino)pyridin-3-yl)(7-(5-(trifluoromethyl)pyrimidin-2-yl)-3-oxa-7,9-diazabicyclo(3.3.1)nonan-9-yl)methanone
  • Analgesics
  • Azabicyclo Compounds
  • TRPV Cation Channels
  • TRPV4 protein, human
  • Thiazoles