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CAPLUS COPYRIGHT 2007 ACS
| TITLE:
| Design of potent, orally available antagonists of the transient receptor potential vanilloid 1. Structure-activity relationships of 2-piperazin-1-yl-1H-benzimidazoles |
| AUTHOR(S):
| Ognyanov, Vassil I.; Balan, Chenera; Bannon, Anthony W.; Bo, Yunxin; Dominguez, Celia; Fotsch, Christopher; Gore, Vijay K.; Klionsky, Lana; Ma, Vu V.; Qian, Yi-Xin; Tamir, Rami; Wang, Xianghong; Xi, Ning; Xu, Shimin; Zhu, Dawn; Gavva, Narender R.; Treanor, James J. S.; Norman, Mark H. |
| CORPORATE SOURCE:
| Department of Chemistry Research and Discovery and Department of Neuroscience, Amgen Inc., Thousand Oaks, CA, 91320-1799, USA |
| SOURCE:
| Journal of Medicinal Chemistry (2006), 49(12), 3719-3742 CODEN: JMCMAR; ISSN: 0022-2623 |
| PUBLISHER:
| American Chemical Society |
| LANGUAGE:
| English |
ABSTRACT:
The vanilloid receptor-1 (VR1 or TRPV1) is a membrane-bound, nonselective cation channel that is predominantly expressed by peripheral neurons sensing painful stimuli. TRPV1 antagonists produce antihyperalgesic effects in animal models of inflammatory and neuropathic pain. The synthesis and the structure-activity relationships of a series of 2-(4-pyridin-2-ylpiperazin-1-yl)-1H-benzo[d]imidazoles I [R1 = H, Me3SiCH2CH2OCH2, PhCH2; R2 = F, Cl, Br, F3C, Me, CN, Me3C, MeO2C, etc.; R3 = H, 4-(2-thiazolyl), 4-(4-pyridyl), 5-(4-F3CC6H4), etc.; R4 = H, Me; R5 = H, H2N, MeCHOH, H2C:CH, etc.; R6 = H, Cl, F3C, etc.] and analogs as novel TRPV1 antagonists have been described. I [R1 = H; R2 = F3C; R3 = 4-(3,4,5-F3C6H2); R4 = (R)-Me; R5 = HOCH2CHOH; R6 = Cl; (II)] was among the most potent analogs in this series. This compd. was orally bioavailable in rats and was efficacious in blocking capsaicin-induced flinch in rats in a dose-dependent manner. II also reversed thermal hyperalgesia in a model of inflammatory pain, which was induced by complete Freund's adjuvant (CFA).
Updated 7/31/2007 8:37:02 AM
