title: Novel GPR119 agonist AS1669058 potentiates insulin secretion from rat islets and has potent anti-diabetic effects in ICR and diabetic db/db mice.
abstract: OBJECTIVE
  G-protein-coupled receptor 119 (GPR119), mainly expressed in pancreatic β-cells, represents a new target for treating type 2 diabetes. GPR119 agonist is known to induce insulin secretion in a glucose-dependent manner by elevating intracellular cAMP concentrations. This study mainly examined the anti-hyperglycemic effect of a novel candidate small-molecule GPR119 agonist AS1669058 2-(4-bromo-2,5-difluorophenyl)-6-methyl-N-[2-(1-oxidopyridin-3-yl)ethyl]pyrimidin-4-amine ethanedioate on ICR mice and diabetic db/db mice.
  
  
  METHODS
  We measured blood glucose, plasma insulin, and insulin content in the pancreas after repeated administration of AS1669058 to db/db mice twice daily for one week.
  
  
  RESULTS
  Under high-concentration glucose conditions, AS1669058 induced insulin secretion in a dose-dependent manner in the hamster pancreatic β-cell line HIT-T15 and in rat pancreatic islets. In addition, AS1669058 increased human insulin promoter activity in NIT-1 cells. In in vivo studies, a single administration of AS1669058 (1 mg/kg) in ICR mice improved oral glucose tolerance based on insulin secretion. Further, 1-week repeated treatment (3 mg/kg, twice daily) in diabetic db/db mice significantly reduced blood glucose levels and tended to increase insulin content in the pancreas.
  
  
  CONCLUSIONS
  These results suggest that AS1669058 has promising potential as an extremely more effective anti-hyperglycemic agent than other compounds we previously reported as GPR119 agonists.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan. hiroyuki.oshima@astellas.com
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Oshima
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yoshida
authors.forename: Takahide
authors.initials: T
authors.lastname: Ohishi
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Matsui
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Tanaka
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yonetoku
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shibasaki
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007004:Hypoglycemic Agents / Q000097:blood / Q000627:therapeutic use*; D007328:Insulin / Q000032:analysis / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011725:Pyridines / Q000097:blood / Q000627:therapeutic use*; D011743:Pyrimidines / Q000097:blood / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*
chemical_list: C579577:AS1669058; D001786:Blood Glucose; C532423:GPR119 protein, rat; C516207:Gpr119 protein, mouse; D007004:Hypoglycemic Agents; D007328:Insulin; D011725:Pyridines; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled