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A novel insulin secretagogue based on a dinucleoside polyphosphate scaffold
Shay Eliahu1, Haim M Barr, Jean Camden
1Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel.
Journal of Medicinal Chemistry
|February 24, 2010
Summary
New dinucleoside polyphosphate analogues show promise for treating type 2 diabetes. Analogue 8 effectively lowers blood glucose and increases insulin levels in rats, offering a potentially safer alternative to existing treatments.
Area of Science:
- Biochemistry
- Pharmacology
- Endocrinology
Background:
- Dinucleoside polyphosphates signal through P2 receptors (P2Rs), acting as potential drug candidates due to enhanced stability and specificity over nucleotides.
- P2Y receptor activation by nucleotides stimulates insulin secretion, highlighting a therapeutic target for diabetes management.
Purpose of the Study:
- To develop and evaluate novel dinucleoside polyphosphate analogues as potential insulin secretagogues for type 2 diabetes treatment.
- Specifically, to synthesize and test analogues 8, 9, and 10 for their P2Y receptor activity, stability, and in vivo efficacy.
Main Methods:
- Synthesis of three dinucleoside polyphosphate analogues: di-(2-MeS)-adenosine-5',5''-P(1),P(4),alpha,beta-methylene-tetraphosphate (8), di-(2-MeS)-adenosine-5',5''-P(1),P(4),beta,gamma-methylene-tetraphosphate (9), and di-(2-MeS)-adenosine-5',5''-P(1),P(3),alpha,beta-methylene triphosphate (10).
- Assay of receptor activity, including EC50 determination for P2Y(1)R agonism.
- Assessment of hydrolytic stability against alkaline phosphatase and human blood serum.
- In vivo studies in rats to evaluate effects on blood glucose and insulin levels following analogue administration.
Main Results:
- Analogues 8 and 9 demonstrated P2Y(1)R agonism with EC50 values of 0.42 and 0.46 microM, respectively; analogue 10 was inactive.
- All analogues (8-10) exhibited complete resistance to alkaline phosphatase hydrolysis over 3 hours at 37°C.
- Analogue 8 displayed enhanced stability in human blood serum compared to ATP, with a half-life of 12.1 hours.
- In rats, analogue 8 significantly reduced blood glucose load and increased insulin levels fourfold, normalizing glucose levels without causing hypoglycemia.
Conclusions:
- Dinucleoside polyphosphate analogues, particularly analogue 8, show significant potential as insulin secretagogues.
- Analogue 8 demonstrates favorable stability and efficacy in reducing hyperglycemia and modulating insulin levels in vivo.
- These findings suggest that analogue 8 could represent a novel and safe therapeutic agent for managing type 2 diabetes.
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