Discovery of a series of indan carboxylic acid glycogen phosphorylase inhibitors |
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Authors: | Stuart NL Bennett Andrew D Campbell Andrew Hancock Craig Johnstone Peter W Kenny Adrian Pickup Alleyn T Plowright Nidhal Selmi Iain Simpson Andy Stocker David P Whalley Paul RO Whittamore |
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Institution: | AstraZeneca, Medicinal Chemistry, Cardiovascular and Gastrointestinal Research Area, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK |
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Abstract: | A series of carboxylic acid glycogen phosphorylase inhibitors, which have potential as oral antidiabetic agents, is described. Defining and applying simple physicochemical design criteria was used to assess the opportunity and to focus synthetic efforts on compounds with the greatest probability of success. The study led to compound 17, which exhibits a good balance of properties including potent inhibition of recombinant human liver glycogen phosphorylase in vitro, a good DMPK profile including excellent bioavailability and low clearance and good in vivo activity in a glucagon challenge model of diabetes in Zucker rats. |
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