Substituted biaryl pyrazoles as sodium channel blockers

Sriram Tyagarajan; Prasun K Chakravarty; Bishan Zhou; Brett Taylor; Michael H Fisher; Mathew J Wyvratt; Kathy Lyons; Tracy Klatt; Xiaohua Li; Sanjeev Kumar; Brande Williams; John Felix; Birgit T Priest; Richard M Brochu; Vivien Warren; McHardy Smith; Maria Garcia; Gregory J Kaczorowski; William J Martin; Catherine Abbadie; Erin McGowan; Nina Jochnowitz; William H Parsons

doi:10.1016/j.bmcl.2010.07.080

Substituted biaryl pyrazoles as sodium channel blockers

Bioorg Med Chem Lett. 2010 Sep 15;20(18):5480-3. doi: 10.1016/j.bmcl.2010.07.080. Epub 2010 Jul 24.

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. sriram_tyagarajan@merck.com

PMID: 20709545
DOI: 10.1016/j.bmcl.2010.07.080

Abstract

Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. A series of low molecular weight biaryl substituted pyrazole carboxamides were identified with good in-vitro potency and in-vivo efficacy. Compound 26, a Nav1.7 blocker has excellent efficacy in the Chung model of neuropathic pain.

MeSH terms

Animals
Dogs
Haplorhini
Humans
Microsomes, Liver / metabolism
NAV1.7 Voltage-Gated Sodium Channel
Neuralgia / drug therapy*
Pyrazoles / chemistry*
Pyrazoles / pharmacokinetics
Pyrazoles / pharmacology
Pyrazoles / therapeutic use*
Rats
Sodium Channel Blockers / chemistry*
Sodium Channel Blockers / pharmacokinetics
Sodium Channel Blockers / pharmacology
Sodium Channel Blockers / therapeutic use*
Sodium Channels / metabolism*
Structure-Activity Relationship

Substances

NAV1.7 Voltage-Gated Sodium Channel
Pyrazoles
SCN9A protein, human
Sodium Channel Blockers
Sodium Channels