N-Alkylidenearylcarboxamides as new potent and selective CB2 cannabinoid receptor agonists with good oral bioavailability

A novel series of N-alkylidenearylcarboxamides 4, a CB2 receptor agonist, were synthesized and evaluated for activity against the human CB2 receptor. In a previous paper, we reported that sulfonamide derivative 1 acted as a potent CB2 receptor agonist (IC50 = 65 nM, EC50 = 19 nM, Emax = 90%). However, compound 1 also exhibited poor metabolic stability in human liver microsomes. During the structural modification of 1, we found that a novel series of N-alkylidenearylcarboxamide, 4-1, had a moderate affinity for the CB2 receptor (IC50 = 260 nM, EC50 = 86 nM, Emax = 100%) and good metabolic stability in human liver microsomes. We explored its analogues to discover compounds with a high affinity for the CB2 receptor and with good oral bioavailability. Among them, compounds 4-9 and 4-27 had high affinities for the human CB2 receptor (CB2 IC50 = 13 nM and 1.2 nM) and a high selectivity for CB2 (CB1 IC50/CB2 IC50 = 270 and 1600); furthermore, significant plasma levels were observed following oral administration in rats (Cmax = 233 ng/mL and 148 ng/mL, respectively, after a dose of 10 mg/kg). Furthermore, compound 4-9 had good oral bioavailability (F = 52%, 3 mg/kg).