title: Nonpeptidic, noncovalent inhibitors of the cysteine protease cathepsin S.
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.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.
authors.forename: Robin L
authors.initials: RL
authors.lastname: Thurmond
authors.forename: Mary Pat
authors.initials: MP
authors.lastname: Beavers
authors.forename: Hui
authors.initials: H
authors.lastname: Cai
authors.forename: Steven P
authors.initials: SP
authors.lastname: Meduna
authors.forename: Darin J
authors.initials: DJ
authors.lastname: Gustin
authors.forename: Siquan
authors.initials: S
authors.lastname: Sun
authors.forename: Harold J
authors.initials: HJ
authors.lastname: Almond
authors.forename: Lars
authors.initials: L
authors.lastname: Karlsson
authors.forename: James P
authors.initials: JP
authors.lastname: Edwards
mesh_terms: D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D000949:Histocompatibility Antigens Class II / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000187:drug effects / Q000378:metabolism; D020128:Inhibitory Concentration 50; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D015853:Cysteine Proteinase Inhibitors; D000949:Histocompatibility Antigens Class II; D007127:Immunoglobulin Constant Regions; D010455:Peptides; D002403:Cathepsins; C028217:cathepsin S