Pyrazolo[3,4-d]pyrimidines containing an extended 3-substituent as potent inhibitors of Lck -: a selectivity insight

被引：64

作者：

Burchat, AF ^{[1
]}

Calderwood, DJ ^{[1
]}

Friedman, MM ^{[1
]}

Hirst, GC ^{[1
]}

Li, BQ ^{[1
]}

Rafferty, P ^{[1
]}

Ritter, K ^{[1
]}

Skinner, BS ^{[1
]}

机构：

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

来源：

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

关键词：

D O I：

10.1016/S0960-894X(02)00196-8

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of para-substituted 3-phenyl pyrazolopyrimidines was synthesized and evaluated as inhibitors of lck. The nature of the substitution affected enzyme selectivity and potency for lck, src, kdr, and tie-2. The para-phenoxyphenyl analogue 2 is an orally active lck inhibitor with a bioavailability of 69% and exhibits an extended duration of action in animal models of T cell inhibition. (C) 2002 Elsevier Science Ltd. All rights reserved.

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页码：1687 / 1690

页数：4

相关论文

共 14 条

[1] Pyrrolo[2,3-d]pyrimidines containing an extended 5-substituent as potent and selective inhibitors of lck I [J].

Arnold, LD ;

Calderwood, DJ ;

Dixon, RW ;

Johnston, DN ;

Kamens, JS ;

Munschauer, R ;

Rafferty, P ;

Ratnofsky, SE .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2000, 10 (19) :2167-2170

[2]

BOLEN JB, 1997, ANNU REV IMMUNOL, V15, P37

[3] Pyrrolo[2,3-d]pyrimidines containing diverse N-7 substituents as potent inhibitors of Lck [J].

Calderwood, DJ ;

Johnston, DN ;

Munschauer, R ;

Rafferty, P .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (12) :1683-1686

[4] Inhibitors of p56lck:: assessing their potential as tools for manipulating T-lymphocyte activation [J].

Dowden, J ;

Ward, SG .

EXPERT OPINION ON THERAPEUTIC PATENTS, 2001, 11 (02) :295-306

[5] Novel method for measurement of submembrane ATP concentration [J].

Gribble, FM ;

Loussouarn, G ;

Tucker, SJ ;

Zhao, C ;

Nichols, CG ;

Ashcroft, FM .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (39) :30046-30049

[6]

HIRST GC, Patent No. 0119829

[7] Tyrosine kinase assays adapted to homogeneous time-resolved fluorescence [J].

Kolb, AJ ;

Kaplita, PV ;

Hayes, DJ ;

Park, YW ;

Pernell, C ;

Major, JS ;

Mathis, G .

DRUG DISCOVERY TODAY, 1998, 3 (07) :333-342

[8] A LYMPHOCYTE-SPECIFIC PROTEIN-TYROSINE KINASE GENE IS REARRANGED AND OVEREXPRESSED IN THE MURINE T-CELL LYMPHOMA LSTRA [J].

MARTH, JD ;

PEET, R ;

KREBS, EG ;

PERLMUTTER, RM .

CELL, 1985, 43 (02) :393-404

[9] PROFOUND BLOCK IN THYMOCYTE DEVELOPMENT IN MICE LACKING P56(LCK) [J].

MOLINA, TJ ;

KISHIHARA, K ;

SIDEROVSKI, DP ;

VANEWIJK, W ;

NARENDRAN, A ;

TIMMS, E ;

WAKEHAM, A ;

PAIGE, CJ ;

HARTMANN, KU ;

VEILLETTE, A ;

DAVIDSON, D ;

MAK, TW .

NATURE, 1992, 357 (6374) :161-164

[10]

NEUMEISTER EN, 1995, MOL CELL BIOL, V15, P3171