Referenced in: none

Automatically associated channels: TRP , TRPV , TRPV1

Title: Discovery of novel 5,5-diarylpentadienamides as orally available transient receptor potential vanilloid 1 (TRPV1) antagonists.

Authors: Osamu Saku, Hiroshi Ishida, Eri Atsumi, Yoshiyuki Sugimoto, Hiroshi Kodaira, Yoshimitsu Kato, Shiro Shirakura, Yoshisuke Nakasato

Journal, date & volume: J. Med. Chem., 2012 Apr 12 , 55, 3436-51

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/22394104

Abstract
We have developed a novel and potent chemical series of 5,5-diphenylpentadienamides for targeting TRPV1 in vitro and in vivo. In this investigation, we examined a variety of replacements for the 5-position of dienamides with the goal of addressing issues related to pharmacokinetics. Our data suggest that substitution with alkoxy groups on the phenyl ring at the 5-position increases their ability to penetrate the blood-brain barrier. This investigation culminated in the discovery of compound (R)-36b, which showed a good pharmacokinetic profile. In vivo, compound (R)-36b was found to be effective at reversing mechanical allodynia in rats in a dose-dependent manner, and it reversed thermal hyperalgesia in a model of neuropathic pain induced by sciatic nerve injury.