text: Several capsaicin analogs of the urea type were developed by acylation of homovanillylamine and related amines with different 4-(α-pyridyl)piperidine-1-acyl chlorides. The presence of a polar amino moiety in the hydrophobic C region of capsacinoids was crucial to couple potency and hydrophilicity, mimicking similar observations that led to the discovery of phenylacetylrinvanil (fig. 3b) from olvanil (fig. 3a). Phenylacetylrinvanil is the most potent capsaicinoid reported to date, ~500-fold more potent than capsaicin. Several other ureas emerged as remarkably active TRPV1 antagonists. Compared with capsazepine, the piperazinyl urea (fig. 5a and 5b) showed a higher selectivity profile against a wide variety of enzymes and channels whereas the related very potent and specific TRPV1 antagonist A-425619 (fig. 5c) could reduce pain associated with inflammation and tissue injury in 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)[16,17] and ABT-102(fig. 5f), compounds that have entered clinical trials.