title: Design and synthesis of dipeptide nitriles as reversible and potent Cathepsin S inhibitors.
abstract: The specificity of the immune response relies on processing of foreign proteins and presentation of antigenic peptides at the cell surface. Inhibition of antigen presentation, and the subsequent activation of T-cells, should, in theory, modulate the immune response. The cysteine protease Cathepsin S performs a fundamental step in antigen presentation and therefore represents an attractive target for inhibition. Herein, we report a series of potent and reversible Cathepsin S inhibitors based on dipeptide nitriles. These inhibitors show nanomolar inhibition of the target enzyme as well as cellular potency in a human B cell line. The first X-ray crystal structure of a reversible inhibitor cocrystallized with Cathepsin S is also reported.
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc. 900 Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877-0368, USA. yward@rdg.boehringer-ingelheim.com
authors.forename: Yancey D
authors.initials: YD
authors.lastname: Ward
authors.forename: David S
authors.initials: DS
authors.lastname: Thomson
authors.forename: Leah L
authors.initials: LL
authors.lastname: Frye
authors.forename: Charles L
authors.initials: CL
authors.lastname: Cywin
authors.forename: Tina
authors.initials: T
authors.lastname: Morwick
authors.forename: Michel J
authors.initials: MJ
authors.lastname: Emmanuel
authors.forename: Renée
authors.initials: R
authors.lastname: Zindell
authors.forename: Daniel
authors.initials: D
authors.lastname: McNeil
authors.forename: Younes
authors.initials: Y
authors.lastname: Bekkali
authors.forename: Marc
authors.initials: M
authors.lastname: Girardot
authors.forename: Matt
authors.initials: M
authors.lastname: Hrapchak
authors.forename: Molly
authors.initials: M
authors.lastname: DeTuri
authors.forename: Kathy
authors.initials: K
authors.lastname: Crane
authors.forename: Della
authors.initials: D
authors.lastname: White
authors.forename: Susan
authors.initials: S
authors.lastname: Pav
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Ming-Hong
authors.initials: MH
authors.lastname: Hao
authors.forename: Christine A
authors.initials: CA
authors.lastname: Grygon
authors.forename: Mark E
authors.initials: ME
authors.lastname: Labadia
authors.forename: Dorothy M
authors.initials: DM
authors.lastname: Freeman
authors.forename: Walter
authors.initials: W
authors.lastname: Davidson
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Hopkins
authors.forename: Maryanne L
authors.initials: ML
authors.lastname: Brown
authors.forename: Denice M
authors.initials: DM
authors.lastname: Spero
authors.forename: Marc
authors.initials: M
authors.lastname: Giradot
mesh_terms: D001402:B-Lymphocytes / Q000187:drug effects; D001667:Binding, Competitive; D002403:Cathepsins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004151:Dipeptides; D004791:Enzyme Inhibitors; D009570:Nitriles; D002403:Cathepsins; C028217:cathepsin S