Hit-to-lead studies: the discovery of potent, orally active, thiophenecarboxamide IKK-2 inhibitors

被引：81
作者：
Baxter, A
Brough, S
Cooper, A
Floettmann, E
Foster, S
Harding, C
Kettle, J
McInally, T
Martin, C
Mobbs, M
Needham, M
Newham, P
Paine, S
St-Gallay, S
Salter, S
Unitt, J
Xue, YF
机构：
[1] AstraZeneca R&D, Loughborough LE11 5RH, Leics, England
[2] AstraZeneca R&D Alderley Pk, Macclesfield SK10 4TG, Cheshire, England
[3] AstraZeneca R&D, Struct Chem Lab, S-43183 Molndal, Sweden
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2004年 / 14卷 / 11期
关键词：
hit-to-lead; IKK inhibitor; kinase;
D O I：
10.1016/j.bmcl.2004.03.058
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
A hit-to-lead optimisation programme was carried out on the thiophenecarboxamide high throughput screening hits 1 and 2 resulting in the discovery of the potent and orally bioavailable IKK-2 inhibitor 22. (C) 2004 Elsevier Ltd. All rights reserved.
引用
收藏
页码：2817 / 2822
页数：6
相关论文
共 21 条
  • [1] The NF-kappa B and I kappa B proteins: New discoveries and insights
    Baldwin, AS
    [J]. ANNUAL REVIEW OF IMMUNOLOGY, 1996, 14 : 649 - 683
  • [2] BAXTER A, Patent No. 0158890
  • [3] CHARMM - A PROGRAM FOR MACROMOLECULAR ENERGY, MINIMIZATION, AND DYNAMICS CALCULATIONS
    BROOKS, BR
    BRUCCOLERI, RE
    OLAFSON, BD
    STATES, DJ
    SWAMINATHAN, S
    KARPLUS, M
    [J]. JOURNAL OF COMPUTATIONAL CHEMISTRY, 1983, 4 (02) : 187 - 217
  • [4] SOLVENT-ACCESSIBLE SURFACES OF PROTEINS AND NUCLEIC-ACIDS
    CONNOLLY, ML
    [J]. SCIENCE, 1983, 221 (4612) : 709 - 713
  • [5] DAVIS REV, Patent No. 209977
  • [6] ATOMIC PHYSICOCHEMICAL PARAMETERS FOR 3-DIMENSIONAL STRUCTURE-DIRECTED QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS .1. PARTITION-COEFFICIENTS AS A MEASURE OF HYDROPHOBICITY
    GHOSE, AK
    CRIPPEN, GM
    [J]. JOURNAL OF COMPUTATIONAL CHEMISTRY, 1986, 7 (04) : 565 - 577
  • [7] IκB kinase-α and -β genes are coexpressed in adult and embryonic tissues but localized to different human chromosomes
    Hu, MCT
    Wang, YP
    [J]. GENE, 1998, 222 (01) : 31 - 40
  • [8] A selective IKK-2 inhibitor blocks NF-κB-dependent gene expression in interleukin-1β-stimulated synovial fibroblasts
    Kishore, N
    Sommers, C
    Mathialagan, S
    Guzova, J
    Yao, M
    Hauser, S
    Huynh, K
    Bonar, S
    Mielke, C
    Albee, L
    Weier, R
    Graneto, M
    Hanau, C
    Perry, T
    Tripp, CS
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (35) : 32861 - 32871
  • [9] Protein kinase inhibition by staurosporine revealed in details of the molecular interaction with CDK2
    Lawrie, AM
    Noble, MEM
    Tunnah, P
    Brown, NR
    Johnson, LN
    Endicott, JA
    [J]. NATURE STRUCTURAL BIOLOGY, 1997, 4 (10) : 796 - 801
  • [10] Severe liver degeneration in mice lacking the IκB kinase 2 gene
    Li, QT
    Van Antwerp, D
    Mercurio, F
    Lee, KF
    Verma, IM
    [J]. SCIENCE, 1999, 284 (5412) : 321 - 325
123