Nonpeptide inhibitors of cathepsin G:: Optimization of a novel β-ketophosphonic acid lead by structure-based drug design

被引:44
作者
Greco, MN [1 ]
Hawkins, MJ
Powell, ET
Almond, HR
Corcoran, TW
de Garavilla, L
Kauffman, JA
Recacha, R
Chattopadhyay, D
Andrade-Gordon, P
Maryanoff, BE
机构
[1] Johnson & Johnson Pharmaceut Res & Dev, Spring House, PA 19477 USA
[2] Univ Alabama Birmingham, Ctr Biophys Sci & Engn, Birmingham, AL 35294 USA
关键词
D O I
10.1021/ja017506h
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The serine protease cathepsin G (EC 3.4.21.20; Cat G), which is stored in the azurophilic granules of neutrophils (polymorphonuclear leukocytes) and released on degranulation, has been implicated in various pathological conditions associated with inflammation. By employing high-throughput screening, we identified β-ketophosphonic acid 1 as a moderate inhibitor of Cat G (IC50 = 4.1 μM). We were fortunate to obtain a cocrystal of 1 with Cat G and solve its structure by X-ray crystallography (3.5 Å). Structural details from the X-ray analysis of 1·Cat G served as a platform for optimization of this lead compound by structure-based drug design. With the aid of molecular modeling, substituents were attached to the 3-position of the 2-naphthyl ring of 1, which occupies the S1 pocket of Cat G, to provide an extension into the hydrophobic S3 region. Thus, we arrived at analogue 7 with an 80-fold potency improvement over 1 (IC50 = 53 nM). From these results, it is evident that the β-ketophosphonic acid unit can form the basis for a novel class of serine protease inhibitors. Copyright © 2002 American Chemical Society.
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收藏
页码:3810 / 3811
页数:2
相关论文
共 38 条
  • [31] MAMMALIAN CHYMOTRYPSIN-LIKE ENZYMES - COMPARATIVE REACTIVITIES OF RAT MAST-CELL PROTEASES, HUMAN AND DOG SKIN CHYMASES, AND HUMAN CATHEPSIN-G WITH PEPTIDE 4-NITROANILIDE SUBSTRATES AND WITH PEPTIDE CHLOROMETHYL KETONE AND SULFONYL FLUORIDE INHIBITORS
    POWERS, JC
    TANAKA, T
    HARPER, JW
    MINEMATSU, Y
    BARKER, L
    LINCOLN, D
    CRUMLEY, KV
    FRAKI, JE
    SCHECHTER, NM
    LAZARUS, GG
    NAKAJIMA, K
    NAKASHINO, K
    NEURATH, H
    WOODBURY, RG
    [J]. BIOCHEMISTRY, 1985, 24 (08) : 2048 - 2058
  • [32] DEGRADATION OF HUMAN-LUNG ELASTIN BY NEUTROPHIL PROTEINASES
    REILLY, CF
    TRAVIS, J
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA, 1980, 621 (01) : 147 - 157
  • [33] DEGRADATION OF CARTILAGE PROTEOGLYCANS BY TISSUE PROTEINASES - PROTEOGLYCAN STRUCTURE AND ITS SUSCEPTIBILITY TO PROTEOLYSIS
    ROUGHLEY, PJ
    BARRETT, AJ
    [J]. BIOCHEMICAL JOURNAL, 1977, 167 (03) : 629 - 637
  • [34] PEPTIDIC PHOSPHORYLATING AGENTS AS IRREVERSIBLE INHIBITORS OF SERINE PROTEASES AND MODELS OF THE TETRAHEDRAL INTERMEDIATES
    SAMPSON, NS
    BARTLETT, PA
    [J]. BIOCHEMISTRY, 1991, 30 (08) : 2255 - 2263
  • [35] 1-NAPHTHYLMETHYLPHOSPHONIC ACID-DERIVATIVES AS OSTEOCLASTIC ACID-PHOSPHATASE INHIBITORS
    SCHWENDER, CF
    BEERS, SA
    MALLOY, E
    DEMAREST, K
    MINOR, L
    LAU, KHW
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1995, 5 (16) : 1801 - 1806
  • [36] VARTIO T, 1981, J BIOL CHEM, V256, P471
  • [37] SYNTHESIS OF PHOSPHONOPEPTIDES AS THROMBIN INHIBITORS
    WANG, CLJ
    TAYLOR, TL
    MICAL, AJ
    SPITZ, S
    REILLY, TM
    [J]. TETRAHEDRON LETTERS, 1992, 33 (50) : 7667 - 7670
  • [38] NOVEL ANTHRAQUINONE INHIBITORS OF HUMAN-LEUKOCYTE ELASTASE AND CATHEPSIN-G
    ZEMBOWER, DE
    KAM, CM
    POWERS, JC
    ZALKOW, LH
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1992, 35 (09) : 1597 - 1605