Synthesis and evaluation of N-phenyl-(2-aminothiazol-4-yl)acetamides with phenoxypropanolamine moiety as selective β3-adrenergic receptor agonists.
In the search for potent and selective human β3-adrenergic receptor (AR) agonists as potential drugs for use in treating obesity and non-insulin dependent (type 2) diabetes, a series of N-phenyl-(2-aminothiazol-4-yl)acetamides with phenoxypropanolamine moiety were prepared and their biological activities against human β3-, β2-, and β1-ARs were evaluated. Among these compounds, N-phenyl-(2-phenylaminothiazol-4-yl)acetamide (4 g), N-phenyl-(2-benzylaminothiazol-4-yl)acetamide (4j), and N-phenyl-[2-(3-methoxyphenyl)aminothiazol-4-yl]acetamide (6g) derivatives showed potent agonistic activity against the β3-AR with functional selectivity over the β1- and β2-ARs. In addition, these compounds exhibited significant hypoglycemic activity in a rodent model of diabetes.
Drug Discovery Research, Astellas Pharma Inc, Ibaraki 305–8585, Japan. tatsuya.maruyama@astellas.com
Tatsuya
T
Maruyama
Kenichi
K
Onda
Takayuki
T
Suzuki
Masahiko
M
Hayakawa
Takumi
T
Takahashi
Tetsuo
T
Matsui
Toshiyuki
T
Takasu
Itsuro
I
Nagase
Mitsuaki
M
Ohta
D000081:Acetamides / Q000737:chemistry*; D000284:Administration, Oral; D058667:Adrenergic beta-3 Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009765:Obesity / Q000188:drug therapy; D050198:Phenoxypropanolamines / Q000737:chemistry*; D018342:Receptors, Adrenergic, beta-1 / Q000737:chemistry / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry / Q000378:metabolism; D022702:Receptors, Adrenergic, beta-3 / Q000737:chemistry* / Q000378:metabolism
D000081:Acetamides; D058667:Adrenergic beta-3 Receptor Agonists; D007004:Hypoglycemic Agents; D050198:Phenoxypropanolamines; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3