ArticleJournal of medicinal chemistry2012
Identification of a promising drug candidate for the treatment of type 2 diabetes based on a P2Y(1) receptor agonist.
Article in Journal of medicinal chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 17 citations in OpenAlex.
- Article
- The Interplay of Endothelial P2Y Receptors in Cardiovascular Health: From Vascular Physiology to Pathology.International journal of molecular sciences · 2022Review
- Synthesis and preclinical validation of novel P2Y1 receptor ligands as a potent anti-prostate cancer agent.Scientific reports · 2019Article
- Synthesis and biological evaluation of stilbene derivatives coupled to NO donors as potential antidiabetic agents.Journal of enzyme inhibition and medicinal chemistry · 2018Article
- Purinergic Signalling: Therapeutic Developments.Frontiers in pharmacology · 2017Review
- Pannexin 1 is required for full activation of insulin-stimulated glucose uptake in adipocytes.Molecular metabolism · 2015Article
- Minireview: Novel aspects of M3 muscarinic receptor signaling in pancreatic β-cells.Molecular endocrinology (Baltimore, Md.) · 2013Review
- Structure-based approaches to ligands for G-protein-coupled adenosine and P2Y receptors, from small molecules to nanoconjugates.Journal of medicinal chemistry · 2013Review
- Molecular Structure of P2Y Receptors: Mutagenesis, Modeling, and Chemical Probes.Wiley interdisciplinary reviews. Membrane transport and signaling · 2012Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
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.
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Registered trials
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