Design, synthesis and biological evaluation of novel analgesic agents targeting both cyclooxygenase and TRPV1

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• 作者：Lin Yan^a ; ^&dagger ; ; Miaobo Pan^b ; ^&dagger ; ; Mian Fu^b ; ^&dagger ; ; Jingjie Wang^b ; ^c ; Wenlong Huang^b ; ^{ydhuangwenlong@126.com" class="auth_mail" title="E-mail the corresponding author} ; Hai Qian^b ; ^{qianhai24@163.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Analgesic ; Transient receptor potential vanilloid type 1 ; Cyclooxygenase ; Hyperthermia
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 February 2016
• 年：2016
• 卷：24
• 期：4
• 页码：849-857
• 全文大小：789 K

文摘

Multitarget-directed ligands might offer certain advantages over traditional single-target drugs and/or drug combinations. In the present study, a series of novel analgesic agents targeting both cyclooxygenase and TRPV1 were prepared and evaluated in an effort to optimize properties of previously described lead compounds from piperazine, ethanediamine cores. These compounds were evaluated for antagonism of hTRPV1 activation by capsaicin and the ability to inhibit Ovine COX-1 and human recombinant COX-2 in vitro. The favorable potentials of these test compounds were further characterized in preliminary analgesic and side-effects tests in vivo. On the basis of comprehensive evaluations, compound 8d which showed strong TRPV1 antagonistic activity, middle COX-2 inhibition, weak ulcerogenic action and had no hyperthermia side-effect was considered as a safe candidate for the further development of analgesic drugs.