Amg 9810

The cinnamide (16, AMG-9810) was identified as a potent TRPV1 antagonist by random screening of a synthetic, proprietary library [70]. (16) was reported to block hTRPV1 activated by various agonists (e.g. capsaicin, acids, heat and endovanilloids), with EC50 values in the hundred nM range, and showed excellent selectivity when assayed against a panel of over 80 targets of pharmaceutical relevance. Given i.p., (16) showed potent activity in rat models of inflammatory injury as well as thermal, and mechanical hyperalgesia. On the other hand (and just like so many others TRPV1 antagonists identified by random screening), (16) showed poor oral absorption and metabolic stability in the rat. To counter these shortcomings, a detailed structure-activity study was undertaken. The lead structure was divided into three sections (benzodioxan-2-yl system, acrylamide core, aryl group) that were independently optimized. Again, the structural simplicity of the hit compound made it possible to generate a large body of structure-activity information. While the acrylamide core could not be modified without detrimental effects on the activity, changes in the two aryl moieties were adequately tolerated. The 7-quinolinyl group was associated with a significant increase in potency, especially in the pH stimulation assay, and the 2-(4-morpholino)-6-(trifluoromethyl)pyridin-3-yl and 2-(piperidin-1-yl)-6-(trifluoromethyl)pyrimidin-3-yl systems proved acceptable replacement for the 4-tert-butylphenyl group in the lead structure. These changes were next combined to generate the analogues (17a) and (17b) that outperformed (16) both in the capsaicin- (IC50 = 2 and 0.4 nM, respectively, versus 17 nM) and the pH-induced assays (IC50 = 1.3 and 1.0 nM, respectively, versus 15 nM).

The pharmacokinetic profile of (16) and its two analogues were investigated in Sprague-Dawley rats. Removal of the metabolically labile tert-butyl group on the aryl moiety slowed metabolism and the rate of clearance. However, the overall half-life of (17a) was unaffected because of a lower volume of distribution. On the other hand, (17b) showed an increased halflife (ca. 3h versus 1 h) compared to (16) and (17a). While the oral bioavailability of (16) was negligible, (17a) and (17b) were better absorbed, with bioavailability values of 39% and 17%, respectively. While undoubtedly improved in terms of pharmacokinetics compared to (16), the bioactivity of (17a) and (17b) awaits validation in vivo.

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