title: Solid-phase parallel synthesis and SAR of 4-amidofuran-3-one inhibitors of cathepsin S: effect of sulfonamides P3 substituents on potency and selectivity.
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 extended S3 pocket and explains the observed selectivity towards cathepsin K.
authors.affiliation: Medivir AB, Lunastigen 7 SE-14144 Huddinge, Sweden.
authors.forename: Susana
authors.initials: S
authors.lastname: Ayesa
authors.forename: Charlotta
authors.initials: C
authors.lastname: Lindquist
authors.forename: Tatiana
authors.initials: T
authors.lastname: Agback
authors.forename: Kurt
authors.initials: K
authors.lastname: Benkestock
authors.forename: Björn
authors.initials: B
authors.lastname: Classon
authors.forename: Ian
authors.initials: I
authors.lastname: Henderson
authors.forename: Ellen
authors.initials: E
authors.lastname: Hewitt
authors.forename: Katarina
authors.initials: K
authors.lastname: Jansson
authors.forename: Anders
authors.initials: A
authors.lastname: Kallin
authors.forename: Dave
authors.initials: D
authors.lastname: Sheppard
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
mesh_terms: D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D003198:Computer Simulation; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D005663:Furans; D011480:Protease Inhibitors; D013449:Sulfonamides; D002403:Cathepsins; C028217:cathepsin S; C534130:CTSK protein, human; D056657:Cathepsin K