title: Preclinical characterization of 55P0251, a novel compound that amplifies glucose-stimulated insulin secretion and counteracts hyperglycaemia in rodents.
abstract: 55P0251 is a novel compound with blood glucose lowering activity in mice, which has been developed from a molecular backbone structure found in herbal remedies. We here report its basic pharmacological attributes and initial progress in unmasking the mode of action.
  
  
  
  Pharmacokinetic properties of 55P0251 were portrayed in several species. First efforts to elucidate the glucose lowering mechanism in rodents included numerous experimental protocols dealing with glucose tolerance, insulin secretion from isolated pancreatic islets and comparison to established drugs.
  
  
  
  A single oral dose of 55P0251 improved glucose tolerance in mice with an ED50between 1.5 and 2 mg/kg (reductions in areas under the curve, 1 mg/kg, -18%; 5 mg/kg, -30%; 27 mg/kg, -47%). Pharmacokinetic studies revealed attractive attributes, including a plasma half-life of approximately 3 hours and a bioavailability of approximately 58% in rats. 55P0251 amplified glucose stimulated insulin release from isolated mouse islets and improved glucose tolerance via increased insulin secretion in rats (increase in area under the insulin curve, +184%). Unlike sulfonylureas and glinides, 55P0251 hardly stimulated insulin release under basal conditions and did not induce hypoglycaemia in vivo, but it amplified the secretory response to glucose and other insulinotropic stimuli (KCl, glucagon-like peptide-1). Comparison to established anti-diabetic agents and examination of interaction with molecular targets (KATPchannel, dipeptidyl peptidase-4, glucagon-like peptide-1 receptor) excluded molecular mechanisms addressed by presently marketed drugs.
  
  
  
  55P0251 is a novel compound that potently counteracts hyperglycaemia in rodents via amplification of glucose-stimulated insulin release.
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Stadlbauer
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Brunmair
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Lehner
authors.affiliation: 55pharma Drug Discovery & Development AG, Vienna, Austria.
authors.forename: Immanuel
authors.initials: I
authors.lastname: Adorjan
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Scherer
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Anton
authors.initials: A
authors.lastname: Luger
authors.affiliation: 55pharma Drug Discovery & Development AG, Vienna, Austria.
authors.forename: Leonhardt
authors.initials: L
authors.lastname: Bauer
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Clemens
authors.identifier: 0000-0001-7168-0013
authors.initials: C
authors.lastname: Fürnsinn
mesh_terms: D000284:Administration, Oral; D000470:Alkaloids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001682:Biological Availability; D001786:Blood Glucose / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D018149:Glucose Intolerance / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D006207:Half-Life; D006943:Hyperglycemia / Q000517:prevention & control*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D054795:Incretins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000819:agonists / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D008810:Mice, Inbred C57BL; D017207:Rats, Sprague-Dawley; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: C000627507:55P0251; D000470:Alkaloids; D001786:Blood Glucose; D015507:Drugs, Investigational; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D054795:Incretins; D007328:Insulin; D054086:KATP Channels; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: antidiabetic drug; drug development; insulin secretion; islets; pharmacokinetics