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PDE-10A inhibitors as insulin secretagogues |
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| Authors: | Cantin Louis-David Magnuson Steven Gunn David Barucci Nicole Breuhaus Marina Bullock William H Burke Jennifer Claus Thomas H Daly Michelle Decarr Lynn Gore-Willse Ann Hoover-Litty Helana Kumarasinghe Ellalahewage S Li Yaxin Liang Sidney X Livingston James N Lowinger Timothy Macdougall Margit Ogutu Herbert O Olague Alan Ott-Morgan Ronda Schoenleber Robert W Tersteegen Adrian Wickens Philip Zhang Zhonghua Zhu Jian Zhu Lei Sweet Laurel J |
| Institution: | Department of Chemistry Research, Bayer Pharmaceuticals Corporation, West Haven, CT 06516, USA. Louis-David.Cantin.Cantin@astrazeneca.com |
| Abstract: | Modulation of cAMP levels has been linked to insulin secretion in preclinical animal models and in humans. The high expression of PDE-10A in pancreatic islets suggested that inhibition of this enzyme may provide the necessary modulation to elicit increased insulin secretion. Using an HTS approach, we have identified quinoline-based PDE-10A inhibitors as insulin secretagogues in vitro. Optimized compounds were evaluated in vivo where improvements in glucose tolerance and increases in insulin secretion were measured. |
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