In this latest publication from the Pfizer labs, the authors describe their continuing efforts to identify urea-based, irreversible inhibitors of fatty acid amide hydrolase (FAAH). Inhibition of FAAH and the concomitant elevation of endogenous levels of fatty acid amides has demonstrated a variety of analgesic effects in animal models. The benefits associated with FAAH inhibition also seem to occur without the desirable effects associated with direct cannabinoid receptor agonism and hence FAAH inhibitors may represent an attractive method of treating pain states in humans.
The Pfizer group had previously identified (see WO 2006/074025) a series of FAAH inhibitors incorporating the biaryl ether piperidine urea scaffold exemplified by PF-3845 (7). In order to minimise the risk associated with irreversible inhibitors of this ilk they sought to identify analogues with improved selectivity and potency in order to reduce any off-target toxicity risks and to minimise the therapeutic dose. In the course of identifying their clinical candidate (23) they focussed on reducing the number of rotatable bonds, and hence the entropic penalty associated with binding, and on identifying those positions in the molecule that could be used to modulate overall polarity without compromising the key lipophilic interactions made within the acyl chain binding pocket. Rigidification of the backbone using the methylenepiperidine (see (23) above) linker led to a unique enhancement in potency (measured as the 2nd order rate constant, kinact/Ki) and equivalent potency at both the human and rat enzymes. Changes to the left-hand side pyridyl ring were poorly tolerated and combination with the 5-CF3 group was shown to be crucial. However, changes to the 3-amino pyridyl component of the urea were better tolerated and alternative substitutions and heterocycles were explored to address potential CYP450 liabilities associated with the pyridyl group. The pyridazine was ultimately shown to have not only reduced CYP inhibtion but also improved potency at the human enzyme. PF-04457845 (23) (clogP = 3.9, PSA = 80) was subsequently identified and shown to be both potent and selective against other serine hydrolases and a CEREP panel. (23) has moderate permeability, low clearance, no apparent Pgp efflux liabilities, excellent PK in rats and dogs, and no glutathione conjugates were observed in hepatocyte incubations. The compound is predicted to be suitable for once daily oral dosing in humans, is highly efficacious in the CFA model of inflammatory pain in rats, and PF-04457845 (23) is now in human clinical trials as a potentially novel analgesic agent (A POC study in osteoarthritis of the knee has been completed but the data from this has not yet been reported).