Solid-phase parallel synthesis and SAR of 4-amidofuran-3-one inhibitors of cathepsin S: effect of sulfonamides P3 substituents on potency and selectivity.
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.
Ayesa
Susana
S
Medivir AB, Lunastigen 7 SE-14144 Huddinge, Sweden.
Lindquist
Charlotta
C
Agback
Tatiana
T
Benkestock
Kurt
K
Classon
Björn
B
Henderson
Ian
I
Hewitt
Ellen
E
Jansson
Katarina
K
Kallin
Anders
A
Sheppard
Dave
D
Samuelsson
Bertil
B
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
D005663:Furans; D011480:Protease Inhibitors; D013449:Sulfonamides; D002403:Cathepsins; C028217:cathepsin S; C534130:CTSK protein, human; D056657:Cathepsin K