title: Pyrazole-based cathepsin S inhibitors with improved cellular potency.
abstract: High potency pyrazole-based noncovalent inhibitors of human cathepsin S (CatS) were developed by modification of the benzo-fused 5-membered ring heterocycles found in earlier series of CatS inhibitors. Although substitutions on this heterocyclic framework had a moderate impact on enzymatic potency, dramatic effects on cellular activity were observed. Optimization afforded indole- and benzothiophene-derived analogues that were high affinity CatS inhibitors (IC(50)=20-40 nM) with good cellular potency (IC(50)=30-340 nM).
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Jianmei
authors.initials: J
authors.lastname: Wei
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Pio
authors.forename: Hui
authors.initials: H
authors.lastname: Cai
authors.forename: Steven P
authors.initials: SP
authors.lastname: Meduna
authors.forename: Siquan
authors.initials: S
authors.lastname: Sun
authors.forename: Yin
authors.initials: Y
authors.lastname: Gu
authors.forename: Wen
authors.initials: W
authors.lastname: Jiang
authors.forename: Robin L
authors.initials: RL
authors.lastname: Thurmond
authors.forename: Lars
authors.initials: L
authors.lastname: Karlsson
authors.forename: James P
authors.initials: JP
authors.lastname: Edwards
mesh_terms: D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology