Solution-phase and solid-phase synthesis of novel transition state inhibitors of coagulation enzymes incorporating a piperidinyl moiety

被引：12

作者：

Adang, AEP ^{[1
]}

Peters, CAM ^{[1
]}

Gerritsma, S ^{[1
]}

de Zwart, E ^{[1
]}

Veeneman, G ^{[1
]}

机构：

[1] Organon Int BV, Lead Discovery Unit, Res & Dev, NL-5340 BH Oss, Netherlands

来源：

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

关键词：

D O I：

10.1016/S0960-894X(99)00179-1

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

2-Amino-3-piperidin-4-yl-propionic acid containing peptidomimetics are potent protease inhibitors when combined with an appropriate keto-thiazole or keto-carboxylic acid moiety. A novel P-1 residue in factor Xa and thrombin inhibitors has been found resulting in IC50 values as low as 0.048 mu M, a factor of ten more potent than Argatroban. Starting with non-chiral synthetic routes, a new stereospecific route was developed as well as a new solid-phase method. (C) 1999 Elsevier Science Ltd. All rights reserved.

引用

页码：1227 / 1232

页数：6

共 13 条

[1] Novel acylguanidine containing thrombin inhibitors with reduced basicity at the P1 moiety [J].

Adang, AEP ;

Lucas, H ;

de Man, APA ;

Engh, RA ;

Grootenhuis, PDJ .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1998, 8 (24) :3603-3608

[2]

ALTENBURGER JM, 1996, Patent No. 713865

[3] SYNTHESIS OF BETA-(4-PYRIDYL)-DL-ALANINE AND OF BETA-(4-PYRIDYL-1-OXIDE)-DL-ALANINE,D-ALANINE, AND L-ALANINE [J].

BIXLER, RL ;

NIEMANN, C .

JOURNAL OF ORGANIC CHEMISTRY, 1958, 23 (04) :575-584

[4]

Cook Nigel S., 1994, Drugs of the Future, V19, P135

[5] Enzyme flexibility, solvent and 'weak' interactions characterize thrombin-ligand interactions: Implications for drug design [J].

Engh, RA ;

Brandstetter, H ;

Sucher, G ;

Eichinger, A ;

Baumann, U ;

Bode, W ;

Huber, R ;

Poll, T ;

Rudolph, R ;

vonderSaal, W .

STRUCTURE, 1996, 4 (11) :1353-1362

[6] LYSINE ANALOGUES AS INHIBITORS OF BACTERIAL GROWTH [J].

HARRIS, JI ;

WORK, TS .

BIOCHEMICAL JOURNAL, 1950, 46 (02) :190-195

[7]

HAUPTMANN J, 1991, PHARMAZIE, V46, P57

[8] PEPTIDE-DERIVED TRANSITION-STATE ANALOG INHIBITORS OF THROMBIN - SYNTHESIS, ACTIVITY AND SELECTIVITY [J].

JETTEN, M ;

PETERS, CAM ;

VISSER, A ;

GROOTENHUIS, PDJ ;

VANNISPEN, JW ;

OTTENHEIJM, HCJ .

BIOORGANIC & MEDICINAL CHEMISTRY, 1995, 3 (08) :1099-1114

[9] CHALLENGES IN THE DEVELOPMENT OF ORALLY BIOAVAILABLE THROMBIN ACTIVE-SITE INHIBITORS [J].

KIMBALL, SD .

BLOOD COAGULATION & FIBRINOLYSIS, 1995, 6 (06) :511-519

[10] Synthesis, evaluation, and crystallographic analysis of L-371,912: A potent and selective active-site thrombin inhibitor [J].

Lyle, TA ;

Chen, ZG ;

Appleby, SD ;

Freidinger, RM ;

Gardell, SJ ;

Lewis, SD ;

Li, Y ;

Lyle, EA ;

Lynch, JJ ;

Mulichak, AM ;

Ng, AS ;

NaylorOlsen, AM ;

Sanders, WM .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1997, 7 (01) :67-72

← 1 2 →