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

Ayesa, Susana; Lindquist, Charlotta; Agback, Tatiana; Benkestock, Kurt; Classon, Bjoern; Henderson, Ian; Hewitt, Ellen; Jansson, Katarina; Kallin, Anders; Sheppard, Dave; Samuelsson, Bertil

doi:10.1016/j.bmc.2008.12.020

Research article2009Peer reviewedOpen access

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

Ayesa, Susana; Lindquist, Charlotta; Agback, Tatiana; Benkestock, Kurt; Classon, Bjoern; Henderson, Ian; Hewitt, Ellen; Jansson, Katarina; Kallin, Anders; Sheppard, Dave; Samuelsson, Bertil

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 pro. le and good cellular potency. Molecular modeling of the most interesting inhibitors describes interactions in the extended S3 pocket and explains the observed selectivity towards cathepsin K. (c) 2008 Elsevier Ltd. All rights reserved.

Keywords

Serin protease; Inhibitors; Cathepsin K; Cathepsin S; Reversible covalent inhibition

Published in

Bioorganic and Medicinal Chemistry
2009, volume: 17, number: 3, pages: 1307-1324
Publisher: PERGAMON-ELSEVIER SCIENCE LTD

SLU Authors

Agback, Tatiana
- Medivir AB

UKÄ Subject classification

Medicinal Chemistry

Publication identifier

DOI: https://doi.org/10.1016/j.bmc.2008.12.020

Permanent link to this page (URI)

https://res.slu.se/id/publ/99467