Bioorganic & Medicinal Chemistry Letters 2010-06-15

Discovery of a series of indan carboxylic acid glycogen phosphorylase inhibitors.

Stuart N L 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 R O Whittamore

Index: Bioorg. Med. Chem. Lett. 20(12) , 3511-4, (2010)

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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.Copyright 2010 Elsevier Ltd. All rights reserved.