| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2015: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Outline of Final Research Achievements |
We attempted to discover novel small molecules that activate Epac2A by in silico similarity search using sulfonylureas and cAMP as queries, followed by the measurement of insulin secretion. Among 170 compounds selected by in silico similarity search, we found ten compounds that stimulate insulin secretion. By Rap1-GTP assay, one compound was indicated to stimulate Rap1 which is a substrate of Epac2A. Based on the structure-activity relationship of its derivatives, we identified compound X as being the most potent insulin secretagogue.
Oral administration of compound X significantly suppressed rises in blood glucose levels after glucose load in wild-type mice and improved glucose tolerance in the Goto-Kakizaki (GK) rat, a model of type 2 diabetes with impaired insulin secretion. Our data indicate that compound X is a novel insulin secretagogue, which serves as a lead compound for development of a new anti-diabetic agent.
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