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lipophilic nature of these compounds translates into a complex pharma-cokinetic profile, compounded by a combination of erratic oral bioavailability and overall poor water solubility. Potent compounds (EC50 in the range of 10 to 200 nM) could be obtained relatively easily in this class, but pre-clinical optimization requires a delicate balance of potency, pharmacokinetics and target specificity. Similar considerations might well apply to other classes of TRPV1 antagonists. (At present, it is unclear if interaction at hERG plagues also other types of TRPV1 antagonists, but the reported inhibition of erg by both capsaicin and arvanil [83] implies that this might be the case.)

Johnson & Johnson piperazine carboxamides

The piperazine-1-carboxamide (13c) [77, 78] exemplifies one of the major problems plaguing synthetic libraries, namely the overall low chemical diversity. Indeed, compound (13c) is very closely related to the Purdue Pharma hit (13a). In contrast to the finding that polar ^-substituents at the anilyl moiety are detrimental for the activity of (13a) [79], (13c) showed potent inhibitory activity (EC50 = 74 nM) against capsaicin-induced activation of hTRPV1 [77, 78]. The published structure-activity relationships for (13c) nicely complement those for (13a), especially with regard to the diamine core. Thus, the cyclic 1,3-diamine motif was essential for activity, with ring expansion, conformational constraint as well as extrusion of one nuclear nitrogen to attain a 3-aminopyrrolidine or a 4-aminopiperidine core, being all detrimental for activity [78].

The biological profile of the optimized lead structure emerging from these studies, compound (15a), was extensively investigated both in vitro and in vivo. The in vitro pattern of activity was in general excellent inasmuch as (15a) could inhibit TRPV1 activation by a variety of stimuli, including reactive oxygen species and phorbol myristoyl acetate (PMA)-induced phosphorylation. Also, oral bioavailability and metabolic stability were acceptable. On the other hand, some intriguing observations were made in a series of animal experiments. For example, (15a) could potently and completely inhibit the inflammatory and painful responses induced by capsaicin. By contrast, it could only partially reverse capsaicin-induced hypothermia [78]. These observations suggest that the blockage by TRPV1 antagonists might be biological end-point specific.

Importantly, (15a) also caused mild hyperthermia, a side-effect that might well arise with other TRPV1-antagonists, and that presumably stems from the inactivation of a constitutionally active endogenous vanilloid pathway. This model is at variance with knock-out (k.o.) TRPV1 mice that have normal temperature. Animals born without a certain receptor, however, frequently adapt by developing alternative pathways. Clearly, these observations are worth further investigation for example by using conditional TRPV1 k.o. animals.

Another interesting finding was that two structurally close analogues of (15a), namely compounds (15b) and (15c), showed marked species-related differences in activity: they behaved as weak antagonists towards hTRPV1, and weak agonists towards rTRPV1 [78]. This observation indicates that great caution should be taken when extrapolating TRPV1 actions from animal models to humans!

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