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

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• 作者：Osamu Saku ; Hiroshi Ishida ; Eri Atsumi ; Yoshiyuki Sugimoto ; Hiroshi Kodaira ; Yoshimitsu Kato ; Shiro Shirakura ; Yoshisuke Nakasato
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：April 12, 2012
• 年：2012
• 卷：55
• 期：7
• 页码：3436-3451
• 全文大小：677K
• 年卷期：v.55,no.7(April 12, 2012)
• ISSN：1520-4804

文摘

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鈥揵rain 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.