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: Shir Yelovitch, Haim M Barr, Jean Camden, Gary A Weisman, Ela Shai, David Varon, Bilha Fischer
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 17 Pg. 7623-35 (Sep 13 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22873688 (Publication Type: Journal Article)

Chemical References

• Blood Glucose
• Hypoglycemic Agents
• Purinergic P2Y Receptor Agonists

Topics

• Animals
• Blood Glucose (analysis)
• Cell Line, Tumor
• Diabetes Mellitus, Experimental (drug therapy)
• Diabetes Mellitus, Type 2 (drug therapy)
• Glucose Tolerance Test
• Humans
• Hypoglycemic Agents (chemistry, pharmacology, therapeutic use)
• Magnetic Resonance Spectroscopy
• Male
• Mice
• Mice, Inbred ICR
• Molecular Structure
• Purinergic P2Y Receptor Agonists (chemistry, pharmacology, therapeutic use)
• Rats
• Rats, Wistar