Novel and potent transforming growth factor beta type I receptor kinase domain inhibitor:: 7-amino 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolol[1,2-b]pyrazol-3-yl)-quinolines

被引:26
作者
Li, HY [1 ]
Wang, Y
Yan, L
Campbell, RM
Anderson, BD
Wagner, JR
Yingling, JM
机构
[1] Lilly Corp Ctr, Lilly Res Labs, Discovery Chem Res, Indianapolis, IN 46285 USA
[2] Lilly Corp Ctr, Lilly Res Labs, Canc Res, Indianapolis, IN 46285 USA
[3] Lilly Corp Ctr, Lilly Res Labs, Lead Optimizat Biol, Indianapolis, IN 46285 USA
关键词
D O I
10.1016/j.bmcl.2004.04.065
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A novel series of 7-amino 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolines was synthesized and their TbetaR-1 inhibitory, p38 MAPK inhibitory, and TbetaR-1-dependent cellular activity were evaluated. Compound 5a was found to be a highly potent in the enzyme assay and TbetaR-1-dependent cellular assays. In addition, dimer (4g), with a urea linker, shows a similar enzyme and cellular activity despite a bulky substitution. (C) 2004 Elsevier Ltd. All rights reserved.
引用
收藏
页码:3585 / 3588
页数:4
相关论文
共 11 条
[1]   Identification of novel inhibitors of the transforming growth factor β1 (TGF-β1) type 1 receptor (ALK5) [J].
Callahan, JF ;
Burgess, JL ;
Fornwald, JA ;
Gaster, LM ;
Harling, JD ;
Harrington, FP ;
Heer, J ;
Kwon, C ;
Lehr, R ;
Mathur, A ;
Olson, BA ;
Weinstock, J ;
Laping, NJ .
JOURNAL OF MEDICINAL CHEMISTRY, 2002, 45 (05) :999-1001
[2]  
GD SEARLE CO, 2000, Patent No. 0031063
[3]   INDUCTION OF C-SIS MESSENGER-RNA AND ACTIVITY SIMILAR TO PLATELET-DERIVED GROWTH-FACTOR BY TRANSFORMING GROWTH-FACTOR-BETA - A PROPOSED MODEL FOR INDIRECT MITOGENESIS INVOLVING AUTOCRINE ACTIVITY [J].
LEOF, EB ;
PROPER, JA ;
GOUSTIN, AS ;
SHIPLEY, GD ;
DICORLETO, PE ;
MOSES, HL .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1986, 83 (08) :2453-2457
[4]  
MINAMI N, 2000, Patent No. 0075131
[5]   β-hydrogen-containing sodium alkoxides as suitable bases in palladium-catalyzed aminations of aryl halides [J].
Prashad, M ;
Hu, B ;
Lu, YS ;
Draper, R ;
Har, D ;
Repic, O ;
Blacklock, TJ .
JOURNAL OF ORGANIC CHEMISTRY, 2000, 65 (08) :2612-2614
[6]  
Salituro FG, 1999, CURR MED CHEM, V6, P807
[7]   Synthesis and activity of new aryl- and heteroaryl- substituted pyrazole inhibitors of the transforming growth factor-b type I receptor kinase domain [J].
Sawyer, JS ;
Anderson, BD ;
Beight, DW ;
Campbell, RM ;
Jones, ML ;
Herron, DK ;
Lampe, JW ;
McCowan, JR ;
McMillen, WT ;
Mort, N ;
Parsons, S ;
Smith, ECR ;
Vieth, M ;
Wier, LC ;
Yan, L ;
Zhang, FM ;
Yingling, JM .
JOURNAL OF MEDICINAL CHEMISTRY, 2003, 46 (19) :3953-3956
[8]  
SAWYER JS, 2002, Patent No. 0294833
[9]  
SAWYER JS, 2004, BIOORG MED CHEM LETT, P14
[10]   GS DOMAIN MUTATIONS THAT CONSTITUTIVELY ACTIVATE T-BETA-R-I, THE DOWNSTREAM SIGNALING COMPONENT IN THE TGF-BETA RECEPTOR COMPLEX [J].
WIESER, R ;
WRANA, JL ;
MASSAGUE, J .
EMBO JOURNAL, 1995, 14 (10) :2199-2208