Discovery of a series of indan carboxylic acid glycogen phosphorylase inhibitors

作者：Bennett Stuart N L; Campbell Andrew D; Hancock Andrew; Johnstone Craig; Kenny Peter W; Pickup Adrian; Plowright Alleyn T^*; Selmi Nidhal; Simpson Iain; Stocker Andy; Whalley David P; Whittamore Paul R O

来源：Bioorganic & Medicinal Chemistry Letters, 2010, 20(12): 3511-3514.

DOI：10.1016/j.bmcl.2010.04.147

• Glycogen phosphorylase
• Antidiabetic agent
• Type 2 diabetes
• Design criteria
• Physicochemical properties

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.

• 出版日期2010-6-15