Development of a promising and safe drug candidate for the treatment of Type 2 Diabetes which reduce

We developed analogues of the P2Y1R receptor agonist 2-MeS-ADP, as potential anti-diabetic drugs. Analogue SY46, was found to be a potent P2Y1R agonist showing no activity at P2Y2/4/6Rs. Analogue SY46 was chemically and metabolically stable to hydrolysis at pH 1.4, and resisted hydrolysis by ectonucleotidases and in human blood serum. IV administration of SY46 in naïve rats decreased blood glucose from 155 mg/dL to normal values ca. 87 mg/dL, unlike glibenclamide which led to sub-normal values (i.e., 63 mg/dL). Similar observations were made for streptozotocin (STZ)-treated and db+/db- mouse models. Furthermore, SY46 inhibits platelet aggregation in vitro and elongates bleeding time in mice, increasing bleeding time vs. that for the commonly used platelet clogging inhibitor, Prasugrel. Oral administration of SY46 to rats increased tail-bleeding volume, similar to aspirin. Hence, SY46 is an effective treatment for type 2 diabetes by reducing both blood glucose levels and platelet aggregation.

Identification of a Promising Insulin Secretagogue Based on a P2Y1 Receptor Agonist. Yelovitch, S, Barr, H. Camden, J.; Weisman, G.; Shai, E.; Varon, D.; Fischer, B. J. Med. Chem. 2012, 55, 7623−7635.