5-Aminopyrimidin-2-ylnitriles as Cathepsin K inhibitors

被引：11

作者：

Morley, Andrew D. ^{[1
]}

Kenny, Peter W. ^{[1
]}

Burton, Brenda ^{[2
]}

Heald, Robert A. ^{[2
]}

MacFaul, Philip A. ^{[1
]}

Mullett, Julia ^{[2
]}

Page, Ken ^{[1
]}

Porres, Soraya S. ^{[2
]}

Ribeiro, Lyn Rosenbrier ^{[1
]}

Smith, Phil ^{[2
]}

Ward, Stuart ^{[2
]}

Wilkinson, Tina J. ^{[2
]}

机构：

[1] AstraZeneca, Mereside, Macclesfield SK10 4TG, Cheshire, England

[2] Argenta Discovery, Harlow CM19 5TR, Essex, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 06期

关键词：

Cathepsin K; Cheminformatics; Covalent inhibitor; Covalent adduct; Cysteine protease; Electrophilicity; Glutathione; Leatherface; Matched molecular pair analysis; MMPA; MoCoM; Molecular core matching; Molecule editor; SMARTS; DRUG DISCOVERY; SCAFFOLD; SMILES;

D O I：

10.1016/j.bmcl.2009.01.110

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of pyrimidine nitrile inhibitors of Cathepsin K with reduced glutathione reactivity has been identified and Molecular Core Matching (MoCoM) has been used to quantify the effect of an amino substituent at C5. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：1658 / 1661

页数：4

共 20 条

[1] Novel purine nitrile derived inhibitors of the cysteine protease cathepsin K [J].

Altmann, E ;

Cowan-Jacob, SW ;

Missbach, M .

JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (24) :5833-5836

[2]

BAILEY A, 2004, Patent No. 000819

[3] Matched molecular pair analysis of activity and properties of glycogen phosphorylase inhibitors [J].

Birch, Alan M. ;

Kenny, Peter W. ;

Simpson, Iain ;

Whittamore, Paul R. O. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (03) :850-853

[4] Drug-protein adducts: An industry perspective on minimizing the potential for drug bioactivation in drug discovery and development [J].

Evans, DC ;

Watt, AP ;

Nicoll-Griffith, DA ;

Baillie, TA .

CHEMICAL RESEARCH IN TOXICOLOGY, 2004, 17 (01) :3-16

[5] Neuronal loss and brain atrophy in mice lacking cathepsins B and L [J].

Felbor, U ;

Kessler, B ;

Mothes, W ;

Goebel, HH ;

Ploegh, HL ;

Bronson, RT ;

Olsen, BR .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (12) :7883-7888

[6]

Grabowska UB, 2005, CURR OPIN DRUG DISC, V8, P619

[7] Applying mechanisms of chemical toxicity to predict drug safety [J].

Guengerich, F. Peter ;

MacDonald, James S. .

CHEMICAL RESEARCH IN TOXICOLOGY, 2007, 20 (03) :344-369

[8]

Kenny PW, 2005, METH PRIN MED CHEM, V22, P271, DOI 10.1002/3527603743.ch11

[9] Matched molecular pairs as a guide in the optimization of pharmaceutical properties; a study of aqueous solubility, plasma protein binding and oral exposure [J].

Leach, Andrew G. ;

Jones, Huw D. ;

Cosgrove, David A. ;

Kenny, Peter W. ;

Ruston, Linette ;

MacFaul, Philip ;

Wood, J. Matthew ;

Colclough, Nicola ;

Law, Brian .

JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (23) :6672-6682

[10] RECAP - Retrosynthetic combinatorial analysis procedure: A powerful new technique for identifying privileged molecular fragments with useful applications in combinatorial chemistry [J].

Lewell, XQ ;

Judd, DB ;

Watson, SP ;

Hann, MM .

JOURNAL OF CHEMICAL INFORMATION AND COMPUTER SCIENCES, 1998, 38 (03) :511-522

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