title: 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%, 3mg/kg).
authors: Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co. Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama-shi, Saitama, Japan. hiroshi.ohta@po.rd.taisho.co.jp
authors: Hiroshi
authors: H
authors: Ohta
authors: Tomoko
authors: T
authors: Ishizaka
authors: Makoto
authors: M
authors: Tatsuzuki
authors: Mitsukane
authors: M
authors: Yoshinaga
authors: Izumi
authors: I
authors: Iida
authors: Yasumitsu
authors: Y
authors: Tomishima
authors: Yoshihisa
authors: Y
authors: Toda
authors: Shuji
authors: S
authors: Saito
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D015394:Molecular Structure; D051381:Rats; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D008024:Ligands; D043885:Receptor, Cannabinoid, CB2