Aryl extensions of thienopyrimidinones as fibroblast growth factor receptor 1 kinase inhibitors

被引:10
作者
Ekkati, Anil R. [1 ]
Mandiyan, Valsan [2 ]
Ravindranathan, Krishna P. [1 ]
Bae, Jae H. [2 ]
Schlessinger, Joseph [2 ]
Jorgensen, William L. [1 ]
机构
[1] Yale Univ, Dept Chem, New Haven, CT 06520 USA
[2] Yale Univ, Dept Pharmacol, Sch Med, New Haven, CT 06520 USA
基金
美国国家卫生研究院;
关键词
FGFR1 kinase inhibitors; Structure-based inhibitor design; Thienopyrimidinones; ATP-competitive small molecule inhibitors; TYROSINE KINASE; SELECTIVE INHIBITORS; DISCOVERY; CANCER; DERIVATIVES; POTENT; DOMAIN;
D O I
10.1016/j.tetlet.2010.12.081
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
Optimization of thienopyrimidinone derivatives as FGFR1 kinase inhibitors is being pursued. The present results confirm predictions of computational modeling that an aryl substituent can be introduced at the 2-position in structure 3. The substituent is anticipated to project deeper into the binding site and provide opportunities for enhanced activity and selectivity. The most potent analog reported herein, 13, has a 4-hydroxyphenyl substituent and yields an IC(50) of 6 mu M for inhibition of phosphorylation by FGFR1 kinase. It was also found that the western anisole-containing substituent in 3 can be replaced by a propionic acid group with no loss in potency and with potentially significant gains in pharmacologically relevant properties. (C) 2010 Elsevier Ltd. All rights reserved.
引用
收藏
页码:2228 / 2231
页数:4
相关论文
共 24 条
  • [1] BAE JH, 3JS2 ID PROT DAT BAN
  • [2] 1-oxo-3-aryl-1H-indene-2-carboxylic acid derivatives as selective inhibitors of fibroblast growth factor receptor-1 tyrosine kinase
    Barvian, MR
    Panek, RL
    Lu, GH
    Kraker, AJ
    Amar, A
    Hartl, B
    Hamby, JM
    Showalter, HDH
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1997, 7 (22) : 2903 - 2908
  • [3] The FGF family: biology, pathophysiology and therapy
    Beenken, Andrew
    Mohammadi, Moosa
    [J]. NATURE REVIEWS DRUG DISCOVERY, 2009, 8 (03) : 235 - 253
  • [4] Discovery of brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinase inhibitor (BMS-540215)
    Cai, Zhen-Wei
    Zhang, Yongzheng
    Borzilleri, Robert M.
    Qian, Ligang
    Barbosa, Stephanie
    Wei, Donna
    Zheng, Xiaoping
    Wu, Lawrence
    Fan, Junying
    Shi, Zhongping
    Wautlet, Barri S.
    Mortillo, Steve
    Jeyaseelan, Robert, Sr.
    Kukral, Daniel W.
    Kamath, Amrita
    Marathe, Punit
    D'Arienzo, Celia
    Derbin, George
    Barrish, Joel C.
    Robl, Jeffrey A.
    Hunt, John T.
    Lombardo, Louis J.
    Fargnoli, Joseph
    Bhide, Rajeev S.
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (06) : 1976 - 1980
  • [5] FGFR3 as a therapeutic target of the small molecule inhibitor PKC412 in hematopoietic malignancies
    Chen, J
    Lee, BH
    Williams, IR
    Kutok, JL
    Mitsiades, CS
    Duclos, N
    Cohen, S
    Adelsperger, J
    Okabe, R
    Coburn, A
    Moore, S
    Huntly, BJP
    Fabbro, D
    Anderson, KC
    Griffin, JD
    Gilliland, DG
    [J]. ONCOGENE, 2005, 24 (56) : 8259 - 8267
  • [6] Cellular signaling by fibroblast growth factor receptors
    Eswarakumar, VP
    Lax, I
    Schlessinger, J
    [J]. CYTOKINE & GROWTH FACTOR REVIEWS, 2005, 16 (02) : 139 - 149
  • [7] Fry DW, 1995, ANTI-CANCER DRUG DES, V10, P607
  • [8] Structure-activity relationships for a novel series of pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors
    Hamby, JM
    Connolly, CJC
    Schroeder, MC
    Winters, RT
    Showalter, HDH
    Panek, RL
    Major, TC
    Olsewski, B
    Ryan, MJ
    Dahring, T
    Lu, GH
    Keiser, J
    Amar, A
    Shen, C
    Kraker, AJ
    Slintak, V
    Nelson, JM
    Fry, DW
    Bradford, L
    Hallak, H
    Doherty, AM
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1997, 40 (15) : 2296 - 2303
  • [9] BIBF 1120: Triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy
    Hilberg, Frank
    Roth, Gerald J.
    Krssak, Martin
    Kautschitsch, Susanna
    Sommergruber, Wolfgang
    Tontsch-Grunt, Ulrike
    Garin-Chesa, Pilar
    Bader, Gerd
    Zoephel, Andreas
    Quant, Jens
    Heckel, Armin
    Rettig, Wolfgang J.
    [J]. CANCER RESEARCH, 2008, 68 (12) : 4774 - 4782
  • [10] FIBROBLAST GROWTH-FACTOR RECEPTOR TYROSINE KINASES - MOLECULAR ANALYSIS AND SIGNAL TRANSDUCTION
    JAYE, M
    SCHLESSINGER, J
    DIONNE, CA
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA, 1992, 1135 (02) : 185 - 199