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

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