Discovery of Novel 5,5-Diarylpentadienamides as Orally Available Transient Receptor Potential Vanilloid 1 (TRPV1) Antagonists

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 (<i>R</i>)-<b>36b</b>, which showed a good pharmacokinetic profile. In vivo, compound (<i>R</i>)-<b>36b</b> 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