A number of companies have reported TRPV1 antagonists containing the 4-aryl-piperazine urea structure. The earliest examples of this chemotype are exemplified by BCTC (8) (IC50 = 34 nM). These structures appear to have been independently discovered by several groups [66-68], possibly an outcome of widely distributed purchased libraries populating corporate compound collections. Anecdotally, the two ureas, 19 and 20, were disclosed almost simultaneously and they retain substantial structural homology with the piperazine ureas [69,70].
Pharmacological evaluation of 8 in rat showed it to be effective in models of inflammatory and neuropathic hyperalgesia, despite its rapid metabolism [41,72]. Separately, a close analog of 8, compound 9 (IC50 = 65 nM), was reported to have significantly improved bioavailability and clearance [16,74], and 9 was also shown to be efficacious in capsaicin evoked allodynia when administered orally (ED50 = 16 mM/Kg). A related compound, 21 (IC50 = 103 nM), from the same group had equivalent activity at TRPV1 but significantly improved clearance; no efficacy data was reported . More recently, several reports have divulged closely related analogues that retain the central piperazine urea core with variations in the flanking aryl moieties [75-81], exemplified by compounds 22 (IC50 = 50 nM), 23 (IC50 = 58 nM), 24, 25 (IC50 = 47 nM), and 26 (IC50 = 374 nM). Notably, the prototypical urea isosteres, hydroxyl-guanidine (23) and cyano-guanidine (24) appear to be tolerated.
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