title: Novel small molecule glucagon-like peptide-1 receptor agonist stimulates insulin secretion in rodents and from human islets.
abstract: OBJECTIVE
  The clinical effectiveness of parenterally-administered glucagon-like peptide-1 (GLP-1) mimetics to improve glucose control in patients suffering from type 2 diabetes strongly supports discovery pursuits aimed at identifying and developing orally active, small molecule GLP-1 receptor agonists. The purpose of these studies was to identify and characterize novel nonpeptide agonists of the GLP-1 receptor.
  
  
  METHODS
  Screening using cells expressing the GLP-1 receptor and insulin secretion assays with rodent and human islets were used to identify novel molecules. The intravenous glucose tolerance test (IVGTT) and hyperglycemic clamp characterized the insulinotropic effects of compounds in vivo.
  
  
  RESULTS
  Novel low molecular weight pyrimidine-based compounds that activate the GLP-1 receptor and stimulate glucose-dependent insulin secretion are described. These molecules induce GLP-1 receptor-mediated cAMP signaling in HEK293 cells expressing the GLP-1 receptor and increase insulin secretion from rodent islets in a dose-dependent manner. The compounds activate GLP-1 receptor signaling, both alone or in an additive fashion when combined with the endogenous GLP-1 peptide; however, these agonists do not compete with radiolabeled GLP-1 in receptor-binding assays. In vivo studies using the IVGTT and the hyperglycemic clamp in Sprague Dawley rats demonstrate increased insulin secretion in compound-treated animals. Further, perifusion assays with human islets isolated from a donor with type 2 diabetes show near-normalization of insulin secretion upon compound treatment.
  
  
  CONCLUSIONS
  These studies characterize the insulinotropic effects of an early-stage, small molecule GLP-1 receptor agonist and provide compelling evidence to support pharmaceutical optimization.
authors.affiliation: Endocrine Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA. sloop_kyle_w@lilly.com
authors.forename: Kyle W
authors.initials: KW
authors.lastname: Sloop
authors.forename: Francis S
authors.initials: FS
authors.lastname: Willard
authors.forename: Martin B
authors.initials: MB
authors.lastname: Brenner
authors.forename: James
authors.initials: J
authors.lastname: Ficorilli
authors.forename: Kathleen
authors.initials: K
authors.lastname: Valasek
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Showalter
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Farb
authors.forename: Julia X C
authors.initials: JX
authors.lastname: Cao
authors.forename: Amy L
authors.initials: AL
authors.lastname: Cox
authors.forename: M Dodson
authors.initials: MD
authors.lastname: Michael
authors.forename: Sonia Maria
authors.initials: SM
authors.lastname: Gutierrez Sanfeliciano
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Tebbe
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Coghlan
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology; D017930:Genes, Reporter; D005934:Glucagon / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1 / Q000502:physiology; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics; D008297:Male; D010281:Parathyroid Hormone / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000819:agonists / Q000235:genetics*; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
chemical_list: C000593833:GLP1R protein, human; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D010281:Parathyroid Hormone; D018027:Receptors, Glucagon; D014660:Vasoactive Intestinal Peptide; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; D008156:Luciferases
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