Synthesis and initial SAR studies of 3,6-disubstituted pyrazolol[1,5-a]pyrimidines:: A new class of KDR kinase inhibitors

被引：121

作者：

Fraley, ME ^{[1
]}

Hoffman, WF

Rubino, RS

Hungate, RW

Tebben, AJ

Rutledge, RZ

McFall, RC

Huckle, WR

Kendall, RL

Coll, KE

Thomas, KA

机构：

[1] Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA

[2] Merck Res Labs, Dept Canc Res, West Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2002年 / 12卷 / 19期

关键词：

D O I：

10.1016/S0960-894X(02)00525-5

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We have synthesized and evaluated the activity of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines as a new class of KDR kinase inhibitors. Starting with screening lead 1, potency against isolated KDR was fully optimized with 3-thienyl and 4-methoxyphenyl substituents at the 6- and 3-positions (3g, KDR IC50 = 19 nM), respectively. The synthesis and SAR of these compounds are described. (C) 2002 Elsevier Science Ltd. All rights reserved.

引用

页码：2767 / 2770

页数：4

共 20 条

[1] SYNTHESIS AND SECRETION OF VASCULAR-PERMEABILITY FACTOR VASCULAR ENDOTHELIAL GROWTH-FACTOR BY HUMAN RETINAL-PIGMENT EPITHELIAL-CELLS [J].

ADAMIS, AP ;

SHIMA, DT ;

YEO, KT ;

YEO, TK ;

BROWN, LF ;

BERSE, B ;

DAMORE, PA ;

FOLKMAN, J .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1993, 193 (02) :631-638

[2] Angiogenesis in cancer and other diseases [J].

Carmeliet, P ;

Jain, RK .

NATURE, 2000, 407 (6801) :249-257

[3] The role of VEGF and thrombospondins in skin angiogenesis [J].

Detmar, M .

JOURNAL OF DERMATOLOGICAL SCIENCE, 2000, 24 :S78-S84

[4]

Drevs J, 2000, CANCER RES, V60, P4819

[5] A CONVENIENT PROCEDURE FOR SMOOTH PALLADIUM-CATALYZED ALLYLIC ALKYLATION BY SODIUM DIMETHYL MALONATE AND CYCLOPENTADIENIDE - A NEW SYNTHESIS OF ALLYLIC SUBSTITUTED CYCLOPENTADIENES [J].

FIAUD, JC ;

MALLERON, JL .

TETRAHEDRON LETTERS, 1980, 21 (46) :4437-4440

[6] ANGIOGENESIS IN CANCER, VASCULAR, RHEUMATOID AND OTHER DISEASE [J].

FOLKMAN, J .

NATURE MEDICINE, 1995, 1 (01) :27-31

[7]

Fong TAT, 1999, CANCER RES, V59, P99

[8] The angiogenic pathway 'vascular endothelial growth factor/flk-I (KDR)-receptor' in rheumatoid arthritis and osteoarthritis [J].

Giatromanolaki, A ;

Sivridis, E ;

Atanassou, N ;

Zois, E ;

Thorpe, PE ;

Brekken, RA ;

Gatter, KC ;

Harris, AL ;

Koukourakis, IM ;

Koukourakis, MI .

JOURNAL OF PATHOLOGY, 2001, 194 (01) :101-108

[9] Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis [J].

Hanahan, D ;

Folkman, J .

CELL, 1996, 86 (03) :353-364

[10] DORMANCY OF MICROMETASTASES - BALANCED PROLIFERATION AND APOPTOSIS IN THE PRESENCE OF ANGIOGENESIS SUPPRESSION [J].

HOLMGREN, L ;

OREILLY, MS ;

FOLKMAN, J .

NATURE MEDICINE, 1995, 1 (02) :149-153

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