Ketoamide-based inhibitors of cysteine protease, cathepsin K: P3 modifications.
J Med Chem
; 47(21): 5057-68, 2004 Oct 07.
Article
in En
| MEDLINE
| ID: mdl-15456249
ABSTRACT
Osteoporosis is a disease characterized by skeletal fragility. Cathepsin K, a lysosomal cysteine protease, has been implicated in the osteoclast mediated bone resorption. Inhibitors of this protease could potentially treat this skeletal disease. The present work describes exploration of the spatial requirements of the S3 subsite by the use of various sterically demanding P3 substituents. Sulfur and oxygen linked heterocycles as well as those without heteroatom linkers were found to provide potent inhibitors of cathepsin K. Representative examples from these series also afforded quite good selectivity ratios against most cathepsins tested. The tolerability of the S3 subsite for sterically demanding groups that provide potency and selectivity enhances the attractiveness of P3 changes to improve the physiochemical properties of inhibitors in the developments of compounds for the treatment of osteoporosis.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cathepsins
/
Amides
/
Ketones
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2004
Type:
Article
Affiliation country:
United States