Identification of Epac2A agonists as novel anti-diabetic agents.

2015 Fiscal Year Final Research Report

• Project/Area Number: 25860749
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Metabolomics
• Research Institution: Kobe University
• Principal Investigator: Sugawara Kenji 神戸大学, 医学(系)研究科(研究院), 研究員 (70645217)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: Epac2A / インスリン分泌 / 糖尿病

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.

Free Research Field

糖尿病学