N-Alkylidenearylcarboxamides as new potent and selective CB 2 cannabinoid receptor agonists with good oral bioavailability

Abstract

A novel series of N-alkylidenearylcarboxamides 4, a CB 2 receptor agonist, were synthesized and evaluated for activity against the human CB 2 receptor. In a previous paper, we reported that sulfonamide derivative 1 acted as a potent CB 2 receptor agonist (IC 50 = 65 nM, EC 50 = 19 nM, E max = 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 CB 2 receptor (IC 50 = 260 nM, EC 50 = 86 nM, E max = 100%) and good metabolic stability in human liver microsomes. We explored its analogues to discover compounds with a high affinity for the CB 2 receptor and with good oral bioavailability. Among them, compounds 4- 9 and 4- 27 had high affinities for the human CB 2 receptor (CB 2 IC 50 = 13 nM and 1.2 nM) and a high selectivity for CB 2 (CB 1 IC 50/CB 2 IC 50 = 270 and 1600); furthermore, significant plasma levels were observed following oral administration in rats ( C max = 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).