Identification of a promising drug candidate for the treatment of type 2 diabetes based on a P2Y1 receptor agonist

Shir Yelovitch, Haim M. Barr, Jean Camden, Gary A. Weisman, Ela Shai, David Varon, Bilha Fischer

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


The activation by extracellular nucleotides of pancreatic P2Y receptors, particularly, the P2Y1R subtype, increases insulin secretion. Therefore, we developed analogues of the P2Y1R receptor agonist 2-MeS-ADP, as potential antidiabetic drugs. Analogue 3A was found to be a potent P2Y1R agonist (EC50 = 0.038 μM vs 0.0025 μM for 2-MeS-ADP) showing no activity at P2Y2/4/6Rs. Analogue 3A was stable at pH 1.4 (t1/2 = 7.3 h) and resistant to hydrolysis vs 2-MeS-ADP by alkaline phosphatase (t1/2 = 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 näve 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.

Original languageEnglish
Pages (from-to)7623-7635
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number17
StatePublished - 13 Sep 2012

Bibliographical note

© 2012 American Chemical Society


FundersFunder number
National Institute of Dental and Craniofacial ResearchR01DE007389


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