Isothiazolopyrimidines and isoxazolopyrimidines as novel multi-targeted inhibitors of receptor tyrosine kinases

被引：27

作者：

Ji, Zhiqin

Ahmed, Asma A.

Albert, Daniel H.

Bouska, Jennifer J.

Bousquet, Peter F.

Cunha, George A.

Glaser, Keith B.

Guo, Jun

Li, Junling

Marcotte, Patrick A.

Moskey, Maria D.

Pease, Lori J.

Stewart, Kent D.

Yates, Melinda

Davidsen, Steven K.

Michaelides, Michael R.

机构：

[1] Abbott Labs, Global Pharmaceut Res & Dev, Abbott Pk, IL 60064 USA

[2] Abbott Biores Ctr, Worcester, MA 01605 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 16期

关键词：

isothiazolopyrimidine; isoxazolopyrimidine; multi-targeted RTK inhibitor;

D O I：

10.1016/j.bmcl.2006.05.057

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of isothiazolopyrimidines and isoxazolopyrimidines were synthesized and identified as potent KDR inhibitors. SAR studies led to isothiazolopyrimidine urea analogs that potently inhibit VEGFR tyrosine kinases (KDR enzymatic and cellular IC50 values below 10 nM) as well as cKIT and TIE2. The selected compounds 8 and 13 display 56% and 48% oral bioavailability in mice, respectively. (c) 2006 Elsevier Ltd. All rights reserved.

引用

页码：4326 / 4330

页数：5

共 20 条

[1]

BILODEAU MT, 2002, EXPERT OPIN INV DRUG, V99, P11393

[2] Oncogenic kinase signalling [J].

Blume-Jensen, P ;

Hunter, T .

NATURE, 2001, 411 (6835) :355-365

[3] New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis [J].

Bold, G ;

Altmann, KH ;

Frei, J ;

Lang, M ;

Manley, PW ;

Traxler, P ;

Wietfeld, B ;

Brüggen, J ;

Buchdunger, E ;

Cozens, R ;

Ferrari, S ;

Furet, P ;

Hofmann, F ;

Martiny-Baron, G ;

Mestan, J ;

Rösel, J ;

Sills, M ;

Stover, D ;

Acemoglu, F ;

Boss, E ;

Emmenegger, R ;

Lässer, L ;

Masso, E ;

Roth, R ;

Schlachter, C ;

Vetterli, W ;

Wyss, D ;

Wood, JM .

JOURNAL OF MEDICINAL CHEMISTRY, 2000, 43 (12) :2310-2323

[4]

Boyer Stephen J., 2002, Current Topics in Medicinal Chemistry, V2, P973, DOI 10.2174/1568026023393273

[5] Thienopyrimidine ureas as novel and potent multitargeted receptor tyrosine kinase inhibitors [J].

Dai, YJ ;

Guo, Y ;

Frey, RR ;

Ji, ZQ ;

Curtin, ML ;

Ahmed, AA ;

Albert, DH ;

Arnold, L ;

Arries, SS ;

Barlozzari, T ;

Bauch, JL ;

Bouska, JJ ;

Bousquet, PF ;

Cunha, GA ;

Glaser, KB ;

Guo, J ;

Li, JL ;

Marcotte, PA ;

Marsh, KC ;

Moskey, MD ;

Pease, LJ ;

Stewart, KD ;

Stoll, VS ;

Tapang, P ;

Wishart, N ;

Davidsen, SK ;

Michaelides, MR .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (19) :6066-6083

[6] Targeting c-kit mutations in solid tumors:: Scientific rationale and novel therapeutic options [J].

Demetri, GD .

SEMINARS IN ONCOLOGY, 2001, 28 (05) :19-26

[7] Angiogenesis inhibitors in clinical development; where are we now and where are we going? [J].

Eskens, FALM .

BRITISH JOURNAL OF CANCER, 2004, 90 (01) :1-7

[8] Protein tyrosine kinase structure and function [J].

Hubbard, SR ;

Till, JH .

ANNUAL REVIEW OF BIOCHEMISTRY, 2000, 69 :373-398

[9] Angiopoietin-1 induces endothelial cell sprouting through the activation of focal adhesion kinase and plasmin secretion [J].

Kim, I ;

Kim, HG ;

Moon, SO ;

Chae, SW ;

So, JN ;

Koh, KN ;

Ahn, BC ;

Koh, GY .

CIRCULATION RESEARCH, 2000, 86 (09) :952-959

[10] Pericyte loss and microaneurysm formation in PDGF-B-deficient mice [J].

Lindahl, P ;

Johansson, BR ;

Leveen, P ;

Betsholtz, C .

SCIENCE, 1997, 277 (5323) :242-245

← 1 2 →