Design and synthesis of potent and selective 5,6-fused heterocyclic thrombin inhibitors

被引：9

作者：

Dominguez, C ^{[1
]}

Duffy, DE ^{[1
]}

Han, Q ^{[1
]}

Alexander, RS ^{[1
]}

Galemmo, RA ^{[1
]}

Park, JM ^{[1
]}

Wong, PC ^{[1
]}

Amparo, EC ^{[1
]}

Knabb, RM ^{[1
]}

Luettgen, J ^{[1
]}

Wexler, RR ^{[1
]}

机构：

[1] Dupont Co, Wilmington, DE 19880 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 1999年 / 9卷 / 07期

关键词：

D O I：

10.1016/S0960-894X(99)00113-4

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Thrombin, a serine protease, plays a central role in the initiation of thrombotic events. We report the design, synthesis, and antithrombotic efficacy of XU817 (7), a nonpeptide 5-(amidino) indole thrombin inhibitor. Utilizing the co-crystal structure of XU817 bound in the active site of thrombin we were able to synthesize analogs with enhanced thrombin affinity. (C) 1999 Elsevier Science Ltd. All rights reserved.

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页码：925 / 930

页数：6

相关论文

共 9 条

[1] 2-STEP FIBRINOGEN-FIBRIN TRANSITION IN BLOOD-COAGULATION [J].

BLOMBACK, B ;

HESSEL, B ;

HOGG, D ;

THERKILDSEN, L .

NATURE, 1978, 275 (5680) :501-505

[2]

CHANG CC, 1990, ORG PREP PROCED INT, V22, P643

[3] The crystal structure of human alpha-thrombin complexed with LY178550, a nonpeptidyl, active site-directed inhibitor [J].

Chirgadze, NY ;

Sall, DJ ;

Klimkowski, VJ ;

Clawson, DK ;

Briggs, SL ;

Hermann, R ;

Smith, GF ;

GiffordMoore, DS ;

Wery, JP .

PROTEIN SCIENCE, 1997, 6 (07) :1412-1417

[4] Derivatives of 5-amidine indole as inhibitors of thrombin catalytic activity [J].

Iwanowicz, EJ ;

Lau, WF ;

Lin, J ;

Roberts, DGM ;

Seiler, SM .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1996, 6 (12) :1339-1344

[5]

KNABB RM, 1992, THROMB HAEMOSTASIS, V67, P56

[6] Antithrombotics serine proteases [J].

Ripka, WC ;

Vlasuk, GP .

ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL 32, 1997, 32 :71-89

[7] AROMATIC AMIDINES - COMPARISON OF THEIR ABILITY TO BLOCK RESPIRATORY SYNCYTIAL VIRUS-INDUCED CELL-FUSION AND TO INHIBIT PLASMIN, UROKINASE, THROMBIN, AND TRYPSIN [J].

TIDWELL, RR ;

GERATZ, JD ;

DUBOVI, EJ .

JOURNAL OF MEDICINAL CHEMISTRY, 1983, 26 (02) :294-298

[8] KINETIC AND CRYSTALLOGRAPHIC STUDIES OF THROMBIN WITH AC-(D)PHE-PRO-BOROARG-OH AND ITS LYSINE, AMIDINE, HOMOLYSINE, AND ORNITHINE ANALOGS [J].

WEBER, PC ;

LEE, SL ;

LEWANDOWSKI, FA ;

SCHADT, MC ;

CHANG, CH ;

KETTNER, CA .

BIOCHEMISTRY, 1995, 34 (11) :3750-3757

[9] Antithrombotic actions of selective inhibitors of blood coagulation factor Xa in rat models of thrombosis [J].

Wong, PC ;

Crain, EJ ;

Nguan, O ;

Watson, CA ;

Racanelli, A .

THROMBOSIS RESEARCH, 1996, 83 (02) :117-126