Identification of (R)-1-(5-tert-Butyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)urea (ABT-102) as a Potent TRPV1 Antagonist for Pain Management
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- 作者：Arthur Gomtsyan ; Erol K. Bayburt ; Robert G. Schmidt ; Carol S. Surowy ; Prisca Honore ; Kennan C. Marsh ; Steven M. Hannick ; Heath A. McDonald ; Jill M. Wetter ; James P. Sullivan ; Michael F. Jarvis ; Connie
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：February 14, 2008
- 年：2008
- 卷：51
- 期：3
- 页码：392 - 395
- 全文大小：111K
- 年卷期：v.51,no.3(February 14, 2008)
- ISSN：1520-4804
文摘
Vanilloid receptor TRPV1 is a cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation by several pharmaceutical companies in an effort to identify novel agents for pain management. Here we report that replacement of substituted benzyl groups by an indan rigid moiety in a previously described N-indazole-N′-benzyl urea series led to a number of TRPV1 antagonists with significantly increased in vitro potency and enhanced drug-like properties. Extensive evaluation of pharmacological, pharmacokinetic, and toxicological properties of synthesized analogs resulted in identification of (R)-7 (ABT-102). Both the analgesic activity and drug-like properties of (R)-7 support its advancement into clinical pain trials.