Optimisation of the P2 pharmacophore in a series of thrombin inhibitors:: Ion-dipole interactions with lysine 60G

被引：10

作者：

Ambler, J ^{[1
]}

Brown, L ^{[1
]}

Cockcroft, XL ^{[1
]}

Grütter, M ^{[1
]}

Hayler, J ^{[1
]}

Janus, D ^{[1
]}

Jones, D ^{[1
]}

Kane, P ^{[1
]}

Menear, K ^{[1
]}

Priestle, J ^{[1
]}

Smith, G ^{[1
]}

Talbot, M ^{[1
]}

Walker, CV ^{[1
]}

Wathey, B ^{[1
]}

机构：

[1] Novartis Horsham Res Ctr, Horsham RH12 4AB, W Sussex, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 1999年 / 9卷 / 09期

关键词：

D O I：

10.1016/S0960-894X(99)00172-9

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The optimisation of the P2 pharmacophore in a series of thrombin inhibitors is described. The interaction of a number of piperidine P2 functionalities with lysine 60G of thrombin is explored with reference to the crystal structure of inhibitor enzyme complexes. A primary ion-dipole interaction between the terminal P2 side chain group and lysine 60G is evoked to explain the SAR in this series. (C) 1999 Elsevier Science Ltd. All rights reserved.

引用

页码：1317 / 1322

页数：6

共 6 条

[1]

Abraham M.H., 1989, J CHEM SOC P2, V2, P1355

[2]

ALLEN M, IN PRESS J MED CHEM

[3] THROMBIN STRUCTURE AND FUNCTION - WHY THROMBIN IS THE PRIMARY TARGET FOR ANTITHROMBOTICS [J].

FENTON, JW ;

OFOSU, FA ;

MOON, DG ;

MARAGANORE, JM .

BLOOD COAGULATION & FIBRINOLYSIS, 1991, 2 (01) :69-75

[4] How good is fluorine as a hydrogen bond acceptor? [J].

Howard, JAK ;

Hoy, VJ ;

OHagan, D ;

Smith, GT .

TETRAHEDRON, 1996, 52 (38) :12613-12622

[5] THROMBIN INHIBITORS .3. CARBOXYL-CONTAINING AMIDE DERIVATIVES OF N-ALPHA-SUBSTITUTED L-ARGININE [J].

KIKUMOTO, R ;

TAMAO, Y ;

OHKUBO, K ;

TEZUKA, T ;

TONOMURA, S ;

OKAMOTO, S ;

HIJIKATA, A .

JOURNAL OF MEDICINAL CHEMISTRY, 1980, 23 (12) :1293-1299

[6]

TURPIE AGG, 1995, THROMB HAEMOSTASIS, V74, P565

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