title: Identification of a novel GPR119 agonist, AS1269574, with in vitro and in vivo glucose-stimulated insulin secretion.
abstract: The G protein-coupled receptor 119 (GPR119) is highly expressed in pancreatic β-cells. On activation, this receptor enhances the effect of glucose-stimulated insulin secretion (GSIS) via the elevation of intracellular cAMP concentrations. Although GPR119 agonists represent promising oral antidiabetic agents for the treatment of type 2 diabetes therapy, they suffer from the inability to adequately directly preserve β-cell function. To identify a new structural class of small-molecule GPR119 agonists with both GSIS and the potential to preserve β-cell function, we screened a library of synthetic compounds and identified a candidate molecule, AS1269574, with a 2,4,6-tri-substituted pyrimidine core. Here, we examined the preliminary in vitro and in vivo effects of AS1269574 on insulin secretion and glucose tolerance. AS1269574 had an EC(50) value of 2.5μM in HEK293 cells transiently expressing human GPR119 and enhanced insulin secretion in the mouse pancreatic β-cell line MIN-6 only under high-glucose (16.8mM) conditions. This contrasted with the action of the sulfonylurea glibenclamide, which also induced insulin secretion under low-glucose conditions (2.8mM). In in vivo studies, a single administration of AS1269574 to normal mice reduced blood glucose levels after oral glucose loading based on the observed insulin secretion profiles. Significantly, AS1269574 did not affect fed and fasting plasma glucose levels in normal mice. Taken together, these results suggest that AS1269574 represents a novel structural class of small molecule, orally administrable GPR119 agonists with GSIS and promising potential for the treatment of type 2 diabetes.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan. shigeru.yoshida@jp.astellas.com
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: Masayuki
authors.initials: M
authors.lastname: Shibasaki
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002460:Cell Line; D004983:Ethanolamines / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D005215:Fasting; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D011743:Pyrimidines / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*
chemical_list: C552740:2-(2-(4-bromophenyl)-6-methylpyrimidin-4-yl)aminoethanol; D001786:Blood Glucose; D004983:Ethanolamines; C519854:GPR119 protein, human; C516207:Gpr119 protein, mouse; D007004:Hypoglycemic Agents; D007328:Insulin; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D005947:Glucose