Discovery of potent, highly selective, and orally bioavailable pyridine carboxamide c-jun NH2-terminal kinase inhibitors

被引:68
作者
Zhao, Hongyu [1 ]
Serby, Michael D. [1 ]
Xin, Zhili [1 ]
Szczepankiewicz, Bruce G. [1 ]
Liu, Mei [1 ]
Kosogof, Christi [1 ]
Liu, Bo [1 ]
Nelson, Lissa T. J. [1 ]
Johnson, Eric F. [1 ]
Wang, Sanyi [1 ]
Pederson, Terry [1 ]
Gum, Rebecca J. [1 ]
Clampit, Jill E. [1 ]
Haasch, Deanna L. [1 ]
Abad-Zapatero, Cele [1 ]
Fry, Elizabeth H. [1 ]
Rondinone, Cristina [1 ]
Trevillyan, James M. [1 ]
Sham, Hing L. [1 ]
Liu, Gang [1 ]
机构
[1] Abbott Labs, Metab Dis Res, Global Pharmaceut Res & Dev, Abbott Pk, IL 60064 USA
关键词
D O I
10.1021/jm060465l
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
C-Jun NH2 terminal kinases (JNKs) are important cell signaling enzymes. JNK1 plays a central role in linking obesity and insulin resistance. JNK2 and JNK3 may be involved in inflammatory and neurological disorders, respectively. Small-molecule JNK inhibitors could be valuable tools to study the therapeutic benefits of inhibiting these enzymes and as leads for potential drugs targeting JNKs. In this report, we disclose a series of potent and highly selective JNK inhibitors with good pharmacokinetic profiles.
引用
收藏
页码:4455 / 4458
页数:4
相关论文
共 32 条
  • [1] Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action
    Aguirre, V
    Werner, ED
    Giraud, J
    Lee, YH
    Shoelson, SE
    White, MF
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (02) : 1531 - 1537
  • [2] The c-Jun NH2-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser307
    Aguirre, V
    Uchida, T
    Yenush, L
    Davis, R
    White, MF
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (12) : 9047 - 9054
  • [3] FUNCTIONAL-GROUP CONTRIBUTIONS TO DRUG RECEPTOR INTERACTIONS
    ANDREWS, PR
    CRAIK, DJ
    MARTIN, JL
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1984, 27 (12) : 1648 - 1657
  • [4] The c-Jun N-terminal protein kinase family of mitogen-activated protein kinases (JNK MAPKs)
    Barr, RK
    Bogoyevitch, MA
    [J]. INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, 2001, 33 (11) : 1047 - 1063
  • [5] JNK: a new therapeutic target for diabetes
    Bennett, BL
    Satoh, Y
    Lewis, AJ
    [J]. CURRENT OPINION IN PHARMACOLOGY, 2003, 3 (04) : 420 - 425
  • [6] Defective T cell differentiation in the absence of Jnk1
    Dong, C
    Yang, DD
    Wysk, M
    Whitmarsh, AJ
    Davis, RJ
    Flavell, RA
    [J]. SCIENCE, 1998, 282 (5396) : 2092 - 2095
  • [7] THE CONDENSATION OF SODIUM NITROMALONALDEHYDE WITH CYANOACETAMIDE
    FANTA, PE
    STEIN, RA
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1955, 77 (04) : 1045 - 1046
  • [8] Design and synthesis of the first generation of novel potent, selective, and in vivo active (benzothiazol-2-yl)acetonitrile inhibitors of the c-Jun N-terminal kinase
    Gaillard, P
    Jeanclaude-Etter, I
    Ardissone, V
    Arkinstall, S
    Cambet, Y
    Camps, M
    Chabert, C
    Church, D
    Cirillo, R
    Gretener, D
    Halazy, S
    Nichols, A
    Szyndralewiez, C
    Vitte, PA
    Gotteland, JP
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (14) : 4596 - 4607
  • [9] Selective interaction of JNK protein kinase isoforms with transcription factors
    Gupta, S
    Barrett, T
    Whitmarsh, AJ
    Cavanagh, J
    Sluss, HK
    Derijard, B
    Davis, RJ
    [J]. EMBO JOURNAL, 1996, 15 (11) : 2760 - 2770
  • [10] A central role for JNK in obesity and insulin resistance
    Hirosumi, J
    Tuncman, G
    Chang, LF
    Görgün, CZ
    Uysal, KT
    Maeda, K
    Karin, M
    Hotamisligil, GS
    [J]. NATURE, 2002, 420 (6913) : 333 - 336