Nonpeptidic, noncovalent inhibitors of the cysteine protease cathepsin S

Robin L Thurmond; Mary Pat Beavers; Hui Cai; Steven P Meduna; Darin J Gustin; Siquan Sun; Harold J Almond; Lars Karlsson; James P Edwards

doi:10.1021/jm0496133

Nonpeptidic, noncovalent inhibitors of the cysteine protease cathepsin S

J Med Chem. 2004 Sep 23;47(20):4799-801. doi: 10.1021/jm0496133.

Authors

Robin L Thurmond¹, Mary Pat Beavers, Hui Cai, Steven P Meduna, Darin J Gustin, Siquan Sun, Harold J Almond, Lars Karlsson, James P Edwards

Affiliation

¹ Johnson & Johnson Pharmaceutical Research and Development L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.

PMID: 15369380
DOI: 10.1021/jm0496133

Abstract

The first nonpeptidic, noncovalent inhibitors of the cysteine protease cathepsin S (CatS) are described. Electronic database searching using the program DOCK generated a screening set of potential CatS inhibitors from which two lead structures were identified as promising starting points for a drug discovery effort. Lead optimization afforded potent (IC(50) < 50 nM) and selective inhibitors of CatS demonstrating cellular activity and reversibility of enzyme inhibition.

MeSH terms

B-Lymphocytes / drug effects
B-Lymphocytes / metabolism
Cathepsins / antagonists & inhibitors*
Cathepsins / chemistry
Cells, Cultured
Cysteine Proteinase Inhibitors / chemistry*
Cysteine Proteinase Inhibitors / pharmacology*
Drug Evaluation, Preclinical / methods
Histocompatibility Antigens Class II / drug effects
Histocompatibility Antigens Class II / metabolism
Humans
Immunoglobulin Constant Regions / drug effects
Immunoglobulin Constant Regions / metabolism
Inhibitory Concentration 50
Peptides / chemistry
Peptides / pharmacology
Protein Conformation
Structure-Activity Relationship

Substances

Cysteine Proteinase Inhibitors
Histocompatibility Antigens Class II
Immunoglobulin Constant Regions
Peptides
Cathepsins
cathepsin S