rats. further research has led to a variety of small-molecule antagonists of trpv1, including the ureas sb-705498 (fig. 5d), sb-452533 (fig. 5e) and abt-102(fig. 5f), compounds that have entered clinical trials. cinnamides figure 6. structure-activity relationship of urea derivatives n-arylcinnamides have emerged as potent and important class of trpv1 antagonists, compound sb-366791, (fig. 6a) shows competitive and specific activity in both human and rat trpv1 receptors overall profile of receptor selectivity much better than that of capsazepine. within this series of compounds, amg-9810 (fig. 6b) exhibited high antagonist potency showing good oral bio-availability in rats and a promising pharmacokinetic profile, boding well for clinical efficacy. another potent blocker from this group is amg0347(fig. 6c)that was shown in a postoperative pain trial to be able to decrease capsaicin-induced heat and mechanical hyperalgesia and to block central trpv1 receptors. carboxamides figure 7. structure-activity relationship of carboxamide derivatives several trpv1 antagonists of the carboxamide type have been discovered. they are structurally quite heterogenous, as exemplified by comparison of the nicotinamide derivative sb-782443 (fig. 7a), the thiazolylcarboxamide (fig. 7b), and the tetrahydropyridylcarboxamide (fig. 7c). sb-782443 (fig. 7a) showed excellent potency at human, guinea pig, and rat trpv1, a favorable in vitro drug metabolism and pharmacokinetics profile, and remarkable in vivo activity in an inflammatory pain model. based on their in vitro profile, several compounds of this class qualified for preclinical development. other derivatives figure 8. structure-activity relationship of unclassified derivatives nonclassic antagonists lack the urea, thiourea, or amide groups typical of the classic trpv1 ligands. two major structural types of nonclassic antagonists have been discovered. first there are the imidazole derivatives. starting from a 4,6-disubstituted benzimidazole lead structure, a series of 4,5-biarylimidazoles capable to block both capsaicin and acid-induced calcium influx in trpv1-expressing chinese hamster ovary cells. imidazole (fig. 8a) was identified as a highly potent and orally bioavailable trpv1. another class are the diaryl ethers and amines. compounds from a quinazoline series can be considered as conformationally restricted analogs of a biarylamide series. in terms of activity 5-isoquinoline was found the most active among and ranked in the order of 5-isoquinoline > 8-quinoline > 8-quinazoline > 8-isoquinoline ≥ cinnoline > phthalazine > quinoxaline > 5-quinoline e.g. amg-517 (fig. 8b), although it lacks any recognizable carbonyl motif it still potently blocks capsaicin, proton, and heat activation of trpv1 in vitro and shows a good tolerability profile. also, the clinical candidates from janssen, abbott and merck pharmaceuticals (fig. 8c) having a 5-aminoisoquinoline group as a common feature suggesting that there is a key interaction of this group at the receptor site for trpv1 antagonist activity. current status in november 2009, the fda approved qutenza (capsaicin, 8% topical patch) for postherpetic neuralgia. clinical trials figure 9. trpv1 antagonists in clinical development as of 2009 as of late 2009, available public information suggests that quite a few are in clinical trials. several biotechnology and pharmaceutical companies are developing trpv1 ligands and the emphasis seems to be on both agonists and antagonists. although the agonists appear to be further along in clinical development. agonists neurogesx has successfully completed three phase iii clinical studies of qutenza (ngx-4010) that met studies primary endpoints. qutenza is a synthetic trans-capsaicin and drug delivery is by a rapid-delivery patch application system neurogesx plans to launch qutenza in the united states in the first half of november 2010. anesiva, another biotechnology company, has completed two phase iii trials of adlea (algrx 4975), an injectable capsaicin. adlea is promising as a pain reliever and both trials showed that adlea's safety profile of adverse events, wound healing, and wound sensory function were similar to placebo over the study duration. antagonists at least seven orally active trpv1 antagonist substances have progressed into clinical development and several more are in preclinical development. the ligand grc-6211, by eli lilly and company-glenmark is the most advanced and is currently in phase iib clinical trials. glaxosmithkline, merck-neurogen, amgen, and astrazeneca are all developing trpv1 antagonist and all are developing substances that have completed phase i trials successfully.