Synthesis and evaluation of novel phenoxypropanolamine derivatives containing acetanilides as potent and selective beta3-adrenergic receptor agonists.
In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of phenoxypropanolamine derivatives containing acetanilides were prepared and their biological activities were evaluated at the human beta3-, beta2-, and beta1-ARs. Several of the analogues (21a, 21b, and 27a) exhibited potent agonistic activity at the beta3-AR. Among the compounds described herein, the N-methyl-1-benzylimidazol-2-ylacetanilide derivative (21b) was found to be the most potent and selective beta3-AR agonist, with an EC(50) value of 0.28 microM and no agonistic activity for either the beta1- or beta2-AR. In addition, 21b showed significant hypoglycemic activity in a rodent diabetic model.
Maruyama
Tatsuya
T
Drug Discovery Research, Astellas Pharma Inc, Tsukuba, Ibaraki, Japan. tatsuya.maruyama@jp.astellas.com
Onda
Kenichi
K
Hayakawa
Masahiko
M
Seki
Norio
N
Takahashi
Takumi
T
Moritomo
Hiroyuki
H
Suzuki
Takayuki
T
Matsui
Tetsuo
T
Takasu
Toshiyuki
T
Nagase
Itsuro
I
Ohta
Mitsuaki
M
D000083:Acetanilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D058665:Adrenergic beta-1 Receptor Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D058667:Adrenergic beta-3 Receptor Agonists; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D050198:Phenoxypropanolamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D000083:Acetanilides; D058665:Adrenergic beta-1 Receptor Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D058667:Adrenergic beta-3 Receptor Agonists; D050198:Phenoxypropanolamines