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PDE-10A inhibitors as insulin secretagogues
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
Affiliation: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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