RESUMO
Efforts to improve the properties of the well studied ketooxazole FAAH inhibitor OL-135 resulted in the discovery of a novel propylpiperidine series of FAAH inhibitors that has a modular design and superior properties to OL-135. The efficacy of one of these compounds was demonstrated in a rat spinal nerve ligation model of neuropathic pain in rats.
Assuntos
Amidoidrolases/antagonistas & inibidores , Oxazóis/farmacologia , Medição da Dor/efeitos dos fármacos , Dor/tratamento farmacológico , Dor/enzimologia , Nervos Espinhais/efeitos dos fármacos , Amidoidrolases/metabolismo , Animais , Sítios de Ligação , Humanos , Oxazóis/síntese química , Oxazóis/química , Piridinas/farmacologia , Ratos , Nervos Espinhais/lesões , Relação Estrutura-AtividadeRESUMO
A series of aryl piperazinyl ureas that act as covalent inhibitors of fatty acid amide hydrolase (FAAH) is described. A potent and selective (does not inhibit FAAH-2) member of this class, JNJ-40355003, was found to elevate the plasma levels of three fatty acid amides: anandamide, oleoyl ethanolamide, and palmitoyl ethanolamide, in the rat, dog, and cynomolgous monkey. The elevation of the levels of these lipids in the plasma of monkeys suggests that FAAH-2 may not play a significant role in regulating plasma levels of fatty acid ethanolamides in primates.