Macrocyclic bisindolylmaleimides as inhibitors of protein kinase C and glycogen synthase kinase-3

被引：63

作者：

Zhang, HC ^{[1
]}

White, KB

Ye, H

McComsey, DF

Derian, CK

Addo, MF

Andrade-Gordon, P

Eckardt, AJ

Conway, BR

Westover, L

Xu, JZ

Look, R

Demarest, KT

Emanuel, S

Maryanoff, BE

机构：

[1] Johnson & Johnson Pharmaceut Res & Dev, Drug Discovery, Spring House, PA 19477 USA

[2] Johnson & Johnson Pharmaceut Res & Dev, Drug Discovery, Raritan, NJ 08869 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2003年 / 13卷 / 18期

关键词：

D O I：

10.1016/S0960-894X(03)00644-9

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Efficient methods were developed to synthesize a novel series of macrocyclic bisindolylmaleimides containing linkers with multiple heteroatoms. Potent inhibitors (single digit nanomolar IC50) for PKC-beta and GSK-3beta were identified, and compounds showed good selectivity over PKC-alpha, -gamma, delta, -epsilon, and -zeta. Representative compound 5a also had high selectivity in a screening panel of 10 other protein kinases. In cell-based functional assays, several compounds effectively blocked interleukin-8 release induced by PKC-beta11 and increased glycogen synthase activity by inhibiting GSK-3beta. (C) 2003 Elsevier Ltd. All rights reserved.

引用

页码：3049 / 3053

页数：5

共 32 条

[1]

Bullock William H., 2002, Current Topics in Medicinal Chemistry, V2, P915, DOI 10.2174/1568026023393255

[2] Effects of a novel glycogen synthase kinase-3 inhibitor on insulin-stimulated glucose metabolism in Zucker diabetic fatty (falfa) rats [J].

Cline, GW ;

Johnson, K ;

Regittnig, W ;

Perret, P ;

Tozzo, E ;

Xiao, L ;

Damico, C ;

Shulman, GI .

DIABETES, 2002, 51 (10) :2903-2910

[3] Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription [J].

Coghlan, MP ;

Culbert, AA ;

Cross, DAE ;

Corcoran, SL ;

Yates, JW ;

Pearce, NJ ;

Rausch, OL ;

Murphy, GJ ;

Carter, PS ;

Cox, LR ;

Mills, D ;

Brown, MJ ;

Haigh, D ;

Ward, RW ;

Smith, DG ;

Murray, KJ ;

Reith, AD ;

Holder, JC .

CHEMISTRY & BIOLOGY, 2000, 7 (10) :793-803

[4] Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death [J].

Cross, DAE ;

Culbert, AA ;

Chalmers, KA ;

Facci, L ;

Skaper, SD ;

Reith, AD .

JOURNAL OF NEUROCHEMISTRY, 2001, 77 (01) :94-102

[5] Inhibitors of glycogen synthase kinase-3: future therapy for unmet medical needs? [J].

Dorronsoro, I ;

Castro, A ;

Martinez, A .

EXPERT OPINION ON THERAPEUTIC PATENTS, 2002, 12 (10) :1527-1536

[6] Glycogen synthase kinase 3: an emerging therapeutic target [J].

Eldar-Finkelman, H .

TRENDS IN MOLECULAR MEDICINE, 2002, 8 (03) :126-132

[7] GLYCOGEN-SYNTHASE KINASE-3 FROM RABBIT SKELETAL-MUSCLE - SEPARATION FROM CYCLIC-AMP-DEPENDENT PROTEIN-KINASE AND PHOSPHORYLASE-KINASE [J].

EMBI, N ;

RYLATT, DB ;

COHEN, P .

EUROPEAN JOURNAL OF BIOCHEMISTRY, 1980, 107 (02) :519-527

[8] Macrocyclic bisindolylmaleimides: Synthesis by inter- and intramolecular alkylation [J].

Faul, MM ;

Winneroski, LL ;

Krumrich, CA ;

Sullivan, KA ;

Gillig, JR ;

Neel, DA ;

Rito, CJ ;

Jirousek, MR .

JOURNAL OF ORGANIC CHEMISTRY, 1998, 63 (06) :1961-1973

[9] A new one step synthesis of maleimides by condensation of glyoxylate esters with acetamides [J].

Faul, MM ;

Winneroski, LL ;

Krumrich, CA .

TETRAHEDRON LETTERS, 1999, 40 (06) :1109-1112

[10]

García-Echeverría C, 2000, MED RES REV, V20, P28, DOI 10.1002/(SICI)1098-1128(200001)20:1<28::AID-MED2>3.0.CO

← 1 2 3 4 →