Pharmacological characterization of a novel, potent, selective, and orally active fatty acid amide hydrolase inhibitor, PKM-833 [(R)-N-(pyridazin-3-yl)-4-(7-(trifluoromethyl)chroman-4-yl)piperazine-1-carboxamide] in rats: Potential for the treatment of inflammatory pain

Abstract

Recently, we identified a novel fatty acid amide hydrolase (FAAH) inhibitor, PKM-833 [(R)-N-(pyridazin-3-yl)-4-(7-(trifluoromethyl)chroman-4-yl)piperazine-1-carboxamide]. The aim of the present study is to characterize the pharmacological profile of PKM-833 in vitro and in vivo. PKM-833 showed potent inhibitory activities against human and rat FAAH with IC50 values of 8.8 and 10 nmol/L, respectively, 200-fold more selectivity against other 137 molecular targets, and irreversible mode of action. In pharmacokinetic and pharmacodynamic studies, PKM-833 showed excellent brain penetration and good oral bioavailability, and elevated anandamide (AEA) concentrations in the rat brain. These data indicate that PKM-833 is a potent, selective, orally active, and brain-penetrable FAAH inhibitor. In behavioral studies using rat models, PKM-833 significantly attenuated formalin-induced pain responses (3 mg/kg) and improved mechanical allodynia in complete freund's adjuvant (CFA)-induced inflammatory pain (0.3-3 mg/kg). On the other hand, PKM-833 did not show the analgesic effects against mechanical allodynia in chronic constriction injury (CCI)-induced neuropathic pain up to 30 mg/kg. Regarding side effects, PKM-833 had no significant effects on catalepsy and motor coordination up to 30 mg/kg. These results indicate that PKM-833 is a useful pharmacological agent that can be used to investigate the role of FAAH and may have therapeutic potential for the treatment of inflammatory pain without undesirable side effects.