title: Azepanone-based inhibitors of human cathepsin L.
abstract: The extension of a previously reported cathepsin K azepanone-based inhibitor template to the design and synthesis of potent and selective inhibitors of the homologous cysteine protease cathepsin L is detailed. Structure-activity studies examining the effect of inhibitor selectivity as a function of the P3 and P2 binding elements of the potent cathepsin K inhibitor 1 revealed that incorporation of either a P3 quinoline-8-carboxamide or a naphthylene-1-carboxamide led to increased selectivity for cathepsin L over cathepsin K. Substitution of the P2 leucine of 1 with either a phenylalanine or a beta-naphthylalanine also resulted in an increased selectivity for cathepsin L over cathepsin K. Molecular modeling studies with the inhibitors docked within the active sites of both cathepsins L and K have rationalized the observed selectivities. Optimization of cathepsin L binding by the combination of the P3 naphthylene-1-carboxamide with the P2 beta-naphthylalanine provided 15, which is a potent, selective, and competitive inhibitor of human cathepsin L with a K(i) = 0.43 nM.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA. Robert.W.Marquis@gsk.com
authors.forename: Robert W
authors.initials: RW
authors.lastname: Marquis
authors.forename: Ian
authors.initials: I
authors.lastname: James
authors.forename: Jin
authors.initials: J
authors.lastname: Zeng
authors.forename: Robert E Lee
authors.initials: RE
authors.lastname: Trout
authors.forename: Scott
authors.initials: S
authors.lastname: Thompson
authors.forename: Attiq
authors.initials: A
authors.lastname: Rahman
authors.forename: Dennis S
authors.initials: DS
authors.lastname: Yamashita
authors.forename: Ren
authors.initials: R
authors.lastname: Xie
authors.forename: Yu
authors.initials: Y
authors.lastname: Ru
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Gress
authors.forename: Simon
authors.initials: S
authors.lastname: Blake
authors.forename: Michael A
authors.initials: MA
authors.lastname: Lark
authors.forename: Shing-Mei
authors.initials: SM
authors.lastname: Hwang
authors.forename: Thaddeus
authors.initials: T
authors.lastname: Tomaszek
authors.forename: Priscilla
authors.initials: P
authors.lastname: Offen
authors.forename: Martha S
authors.initials: MS
authors.lastname: Head
authors.forename: Maxwell D
authors.initials: MD
authors.lastname: Cummings
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Veber
mesh_terms: D000577:Amides / Q000737:chemistry; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D011804:Quinolines / Q000737:chemistry; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000577:Amides; D001381:Azepines; D015853:Cysteine Proteinase Inhibitors; D011804:Quinolines; D013450:Sulfones; C506290:naphthalene-2-carboxylic acid (2-naphthalen-2-yl-1-(3-oxo-1-(pyridine-2-sulfonyl)azepan-4-ylcarbamoyl)ethyl)amide; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L