SB-366791 (18) emerged from screening an in-house library as a potent competitive inhibitor of both hTRPV1 and rTRPV1, endowed with superior target selectivity compared to capsazepine [84]. Structure-activity relationships of SB-366791 remain to be reported.


Abbott lead

The 7-hydroxynaphthalenyl urea (19) was identified by high-throughput screening (HTS) of a chemical library as a potent (EC50 = 22 nM) inhibitor of hTRPV1 [85]. This compound, however, was inactive in animal models of inflammatory pain, and was not orally available [85]. A structure-activity study was therefore undertaken, capitalizing on the assumption that the phenolic hydroxyl, though critical for activity, was also providing a potential site for metabolism, and should therefore be replaced with heterocyclic fragments having a similar charge distribution. Eight hetero(bi)cyclic aro-matics were evaluated as 7-hydroxynaphthyl-equivalents, with the 5-isoquinolyl giving the most active analogue. Furthermore, the replacement of the N'-aryl group with an N'-benzyl group enhanced activity, and the p-CF3 group was discovered to be an excellent replacement for the m-me-thylthio substituent, apparently another site of metabolic lability.

Compound (20) eventually emerged as an optimized lead (EC50 = 4nM) with satisfactory pharmacokinetic and solubility properties as well as potent activity in animal models of visceral and chronic inflammatory pain [85].

(20) R1 = H; R2 = CF3 (22a) R1 = CF3; R2 = Cl (22b) R1 = H; R2 = t-Bu

(20) R1 = H; R2 = CF3 (22a) R1 = CF3; R2 = Cl (22b) R1 = H; R2 = t-Bu


Johnson & Johnson leads

The benzamide (8) and urea (21) emerged as hTRPV1 antagonists from efforts aimed at the optimization of the agonist activity of the pyridin-2-ylcarboxamide (7) [71]. Compounds (8) and (21) showed submicromolar affinity for TRPV1 (as measured by displacement of [3H]RTX from hTRPV1), but only modest antagonist potency (IC50 = 24 mM for 8 and 0.49 mM for 21). Therefore, structural modification was pursued using both affinity - (displacement of RTX binding) and functional assays (antagonism of capsaicin-evoked Ca2+ influx). The correlation between the K and the IC50 values suggested a common binding site for these compounds and the agonists.

Similar to capsaicin, (8) and (21) showed a recognizable polar head, a linking group and a lipophilic tail, and these regions were independently explored. Not unexpectedly, the results showed that the proper positioning of the heterocyclic moiety and the aryl moiety containing the 'cannabinoid-like' n-pentyl chain were critical for activity, while N-methylation of the amide and urea nitrogens was detrimental. The n-pentyl chain of the distal urea (benzamide) end could be replaced by a CF3 group, but not by polar groups or hydrogen, in accordance with the critical role of added lipophili-city. Based on these observations, compounds (22a) and (22b) endowed with subnanomolar binding affinity (0.8 and 0.5 nM, respectively) and low nano-molar functional activity were eventually discovered. It is interesting to note that the final lead structure (22a) showed a vanillyl-type 'lipophilic' tail, blurring the distinction between the hydrophilic and the lipophilic endings of the hit structure, and leading to an overall similarity to capsaicin [71].

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