Solid-phase parallel synthesis and SAR of 4-amidofuran-3-one inhibitors of cathepsin S: effect of sulfonamides P3 substituents on potency and selectivity

S Ayesa, C Lindquist, T Agback, K Benkestock…

Index: Ayesa, Susana; Lindquist, Charlotta; Agback, Tatiana; Benkestock, Kurt; Classon, Bjoern; Henderson, Ian; Hewitt, Ellen; Jansson, Katarina; Kallin, Anders; Sheppard, Dave; Samuelsson, Bertil Bioorganic and Medicinal Chemistry, 2009 , vol. 17, # 3 p. 1307 - 1324

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Citation Number: 14

Abstract

Highly potent and selective 4-amidofuran-3-one inhibitors of cathepsin S are described. The synthesis and structure–activity relationship of a series of inhibitors with a sulfonamide moiety in the P3 position is presented. Several members of the series show sub-nanomolar inhibition of the target enzyme as well as an excellent selectivity profile and good cellular potency. Molecular modeling of the most interesting inhibitors describes interactions in the ...