Design, synthesis, and biological evaluation of peptidomimetic inhibitors of factor XIa as novel anticoagulants

被引：63

作者：

Lin, Jian ^{[1
]}

Deng, Hongfeng ^{[1
]}

Jin, Lei ^{[1
]}

Pandey, Pramod ^{[1
]}

Quinn, Jesse ^{[1
]}

Cantin, Susan ^{[1
]}

Rynkiewicz, Michael J. ^{[1
]}

Gorga, Joan C. ^{[1
]}

Bibbins, Frank ^{[1
]}

Celatka, Cassandra A. ^{[1
]}

Nagafuji, Pamela ^{[1
]}

Bannister, Thomas D. ^{[1
]}

Meyers, Harold V. ^{[1
]}

Babine, Robert E. ^{[1
]}

Hayward, Neil J. ^{[1
]}

Weaver, David ^{[1
]}

Benjamin, Howard ^{[1
]}

Stassen, Frans ^{[1
]}

Abdel-Meguid, Sherin S. ^{[1
]}

Strickler, James E. ^{[1
]}

机构：

[1] Daiichi Asubio Med Res Labs LLC, Cambridge, MA 02139 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 26期

关键词：

D O I：

10.1021/jm060978s

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Human coagulation factor XIa (FXIa), a serine protease activated by site-specific cleavage of factor XI by thrombin, FXIIa, or autoactivation, is a critical enzyme in the amplification phase of the coagulation cascade. To investigate the potential of FXIa inhibitors as safe anticoagulants, a series of potent, selective peptidomimetic inhibitors of FXIa were designed and synthesized. Some of these inhibitors showed low nanomolar FXIa inhibitory activity with > 1000-fold FXa selectivity and > 100-fold thrombin selectivity. The X-ray structure of one of these inhibitors, 36, demonstrates its unique binding interactions with FXIa. Compound 32 caused a doubling of the activated partial thromboplastin time in human plasma at 2.4 mu M and was efficacious in a rat model of venous thrombosis. These data suggest that factor XIa plays a significant role in venous thrombosis and may be a suitable target for the development of antithrombotic therapy.

引用

页码：7781 / 7791

页数：11

共 48 条

[1]

ABDELMEGUID SS, 2004, Patent No. 04089297

[2] Peptidyl alpha-keto thiazole as potent thrombin inhibitors [J].

Akiyama, Y ;

Tsutsumi, S ;

Hatsushiba, E ;

Ohuchi, S ;

Okonogi, T .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1997, 7 (05) :533-538

[3]

ASKAI R, 1991, NEW ENGL J MED, V325, P153

[4] DENTAL SURGERY IN PATIENTS WITH SEVERE FACTOR-XI DEFICIENCY WITHOUT PLASMA REPLACEMENT [J].

BERLINER, S ;

HOROWITZ, I ;

MARTINOWITZ, U ;

BRENNER, B ;

SELIGSOHN, U .

BLOOD COAGULATION & FIBRINOLYSIS, 1992, 3 (04) :465-468

[5] Treatment of factor XI inhibitor using recombinant activated factor VIIa [J].

Bern, MM ;

Sahud, M ;

Zhukov, O ;

Qu, K ;

Mitchell, W .

HAEMOPHILIA, 2005, 11 (01) :20-25

[6]

BERRYMAN KA, 1997, Patent No. 9748687

[7] Thrombin-activatable fibrinolysis inhibitor (TAFI, plasma procarboxypeptidase B, procarboxypeptidase R, procarboxypeptidase U) [J].

Bouma, BN ;

Marx, PF ;

Mosnier, LO ;

Meijers, JCM .

THROMBOSIS RESEARCH, 2001, 101 (05) :329-354

[8] Role of blood coagulation factor XI in downregulation of fibrinolysis [J].

Bouma, BN ;

Meijers, JCM .

CURRENT OPINION IN HEMATOLOGY, 2000, 7 (05) :266-272

[9] THE COAGULATION CASCADE - INITIATION, MAINTENANCE, AND REGULATION [J].

DAVIE, EW ;

FUJIKAWA, K ;

KISIEL, W .

BIOCHEMISTRY, 1991, 30 (43) :10363-10370

[10] The protein C pathway [J].

Esmon, CT .

CHEST, 2003, 124 (03) :26S-32S

← 1 2 3 4 5 →