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Azepanone-based inhibitors of human cathepsin S: optimization of selectivity via the P2 substituent.
Bioorg Med Chem Lett
August 2011
GlaxoSmithKline, King of Prussia, PA 19406, United States.
A series of azepanone inhibitors of cathepsin S is described. Selectivity over both cathepsin K and cathepsin L was achieved by varying the P2 substituent. Ultimately, a balanced potency and selectivity profile was achieved in compound 39 possessing a 1-methylcyclohexyl alanine at P2 and nicotinamide as the P' substituent.
View Article and Find Full Text PDFStructure activity relationships of 5-, 6-, and 7-methyl-substituted azepan-3-one cathepsin K inhibitors.
J Med Chem
March 2006
Department of Medicinal Chemistry, GlaxoSmithKline, 1250 S. Collegeville Rd, Collegeville, Pennsylvania 19426, USA.
The syntheses, in vitro characterizations, and rat and monkey in vivo pharmacokinetic profiles of a series of 5-, 6-, and 7-methyl-substituted azepanone-based cathepsin K inhibitors are described. Depending on the particular regiochemical substitution and stereochemical configuration, methyl-substituted azepanones were identified that had widely varied cathepsin K inhibitory potency as well as pharmacokinetic properties compared to the 4S-parent azepanone analogue, 1 (human cathepsin K, K(i,app) = 0.16 nM, rat oral bioavailability = 42%, rat in vivo clearance = 49.
View Article and Find Full Text PDFAzepanone-based inhibitors of human cathepsin L.
J Med Chem
November 2005
Department of Medicinal Chemistry, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
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.
View Article and Find Full Text PDFAn azepanone-based inhibitor of human cathepsin K with improved oral bioavailability in the rat and the monkey.
Mol Pharm
January 2004
Departments of Medicinal Chemistry, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA.
Azepanone-based inhibitors of human and rat cathepsin K.
J Med Chem
April 2001
Department of Medicinal Chemistry, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, USA.
The synthesis, in vitro activities, and pharmacokinetics of a series of azepanone-based inhibitors of the cysteine protease cathepsin K (EC 3.4.22.
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