title: Identification of a promising drug candidate for the treatment of type 2 diabetes based on a P2Y(1) receptor agonist.
abstract: The activation by extracellular nucleotides of pancreatic P2Y receptors, particularly, the P2Y(1)R subtype, increases insulin secretion. Therefore, we developed analogues of the P2Y(1)R receptor agonist 2-MeS-ADP, as potential antidiabetic drugs. Analogue 3A was found to be a potent P2Y(1)R agonist (EC(50) = 0.038 μM vs 0.0025 μM for 2-MeS-ADP) showing no activity at P2Y(2/4/6)Rs. Analogue 3A was stable at pH 1.4 (t(1/2) = 7.3 h) and resistant to hydrolysis vs 2-MeS-ADP by alkaline phosphatase (t(1/2) = 6 vs 4.5 h), human e-NPP1 (4% vs 16% hydrolysis after 20 min), and human blood serum (30% vs 50% hydrolysis after 24 h). Intravenous administration of 3A in naive rats decreased blood glucose from 155 mg/dL to normal values, ca. 87 mg/dL, unlike glibenclamide, leading to subnormal values (i.e., 63 mg/dL). Similar observations were made for streptozotocin (STZ)-treated and db(+)/db(-) mouse models. Furthermore, 3A inhibits platelet aggregation in vitro and elongates bleeding time in mice (iv administration of 30 mg of 3A/kg), increasing bleeding time to 16 vs 9 min for Prasugrel. Oral administration of 30 mg/kg 3A to rats increased tail bleeding volume, similar to aspirin. These findings suggest that 3A may be an effective treatment for type 2 diabetes by reducing both blood glucose levels and platelet aggregation.
authors.affiliation: Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel.
authors.forename: Shir
authors.initials: S
authors.lastname: Yelovitch
authors.forename: Haim M
authors.initials: HM
authors.lastname: Barr
authors.forename: Jean
authors.initials: J
authors.lastname: Camden
authors.forename: Gary A
authors.initials: GA
authors.lastname: Weisman
authors.forename: Ela
authors.initials: E
authors.lastname: Shai
authors.forename: David
authors.initials: D
authors.lastname: Varon
authors.forename: Bilha
authors.initials: B
authors.lastname: Fischer
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D045744:Cell Line, Tumor; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D058912:Purinergic P2Y Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D058912:Purinergic P2Y Receptor Agonists