title: Discovery of novel acetanilide derivatives as potent and selective beta3-adrenergic receptor agonists.
abstract: 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 acetanilide-based analogues were prepared and their biological activities were evaluated at the human beta3-, beta2-, and beta1-ARs. Among these compounds, 2-pyridylacetanilide (2f), pyrimidin-2-ylacetanilide (2u), and pyrazin-2-ylacetanilide (2v) derivatives exhibited potent agonistic activity at the beta3-AR with functional selectivity over the beta1- and beta2-ARs. In particular, compound 2u was found to be the most potent and selective beta3-AR agonist with an EC(50) value of 0.11 microM and no agonistic activity for either the beta1- or beta2-AR. In addition, 2f, 2u, and 2v showed significant hypoglycemic activity in a rodent diabetic model.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. tatsuya.maruyama@jp.astellas.com
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Maruyama
authors.forename: Kenichi
authors.initials: K
authors.lastname: Onda
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hayakawa
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Matsui
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takasu
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ohta
mesh_terms: 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; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C541994:4'-(2-((2-hydroxy-3-(4-hydroxyphenoxy)propyl)amino)ethyl)-2-(2-pyridyl)acetanilide; C541997:4'-(2-((2-hydroxy-3-(4-hydroxyphenoxy)propyl)amino)ethyl)-2-(pyrazin-2-yl)acetanilide; C541996:4'-(2-((2-hydroxy-3-(4-hydroxyphenoxy)propyl)amino)ethyl)-2-(pyrimidin-2-yl)acetanilide; D000083:Acetanilides; D058665:Adrenergic beta-1 Receptor Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D058667:Adrenergic beta-3 Receptor Agonists; D011719:Pyrazines; D011725:Pyridines; D011743:Pyrimidines