title: Synthesis and evaluation of novel phenylethanolamine derivatives containing acetanilides as potent and selective beta3-adrenergic receptor agonists.
abstract: In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential pharmacotherapies for the treatment of obesity and non-insulin dependent (type II) diabetes, we prepared a novel series of phenylethanolamine derivatives containing acetanilides and evaluated their biological activities at the human beta3-, beta2-, and beta1-ARs. Among these compounds, the 6-amino-2-pyridylacetanilide (36b), 2-amino-5-methylthiazol-4-ylacetanilide (36g), and 5-amino-1,2,4-thiadiazol-3-ylacetanilide (36h) derivatives showed potent agonistic activity at the beta3-AR with functional selectivity over the beta1- and beta2-ARs. In addition, these compounds exhibited significant hypoglycemic activity in a rodent diabetic model.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc, Tsukuba, Ibaraki, 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: Takayuki
authors.initials: T
authors.lastname: Suzuki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kimizuka
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Matsui
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takasu
authors.forename: Itsuro
authors.initials: I
authors.lastname: Nagase
authors.forename: Noritaka
authors.initials: N
authors.lastname: Hamada
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ohta
mesh_terms: D000322:Adrenergic Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D058667:Adrenergic beta-3 Receptor Agonists; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D010627:Phenethylamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism
chemical_list: D000322:Adrenergic Agonists; D058667:Adrenergic beta-3 Receptor Agonists; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D010627:Phenethylamines; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3