Identification of a promising drug candidate for the treatment of type 2 diabetes based on a P2Y _1 receptor agonist

摘要

The activation by extracellular nucleotides of pancreatic P2Y receptors, particularly, the P2Y _1R subtype, increases insulin secretion. Therefore, we developed analogues of the P2Y _1R receptor agonist 2-MeS-ADP, as potential antidiabetic drugs. Analogue 3A was found to be a potent P2Y _1R 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 n?ve 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.