Discovery of a factor Xa inhibitor (3R,4R)-1-(2,2-difluoro-ethyl)-pyrrolidine-3,4-dicarboxylic acid 3-[(5-chloro-pyridin-2-yl)-amide] 4-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide} as a clinical candidate

被引：30

作者：

Anselm, Lilli ^{[1
]}

Banner, David W. ^{[1
]}

Benz, Joerg ^{[1
]}

Zbinden, Katrin Groebke ^{[1
]}

Himber, Jacques ^{[1
]}

Hilpert, Hans ^{[1
]}

Huber, Walter ^{[1
]}

Kuhn, Bernd ^{[1
]}

Mary, Jean-Luc ^{[1
]}

Otteneder, Michael B. ^{[1
]}

Panday, Narendra ^{[1
]}

Ricklin, Fabienne ^{[1
]}

Stahl, Martin ^{[1
]}

Thomi, Stefan ^{[1
]}

Haap, Wolfgang ^{[1
]}

机构：

[1] F Hoffmann La Roche Ltd, Pharma Res, CH-4070 Basel, Switzerland

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 17期

关键词：

Factor Xa inhibitors; Anticoagulation; Structure based design; X-ray analysis; VENOUS-THROMBOEMBOLISM; ANTITHROMBOTIC AGENT; ORAL ANTICOAGULANTS; MAXIMUM-LIKELIHOOD; IN-VITRO; THROMBIN; PREVENTION; POTENT; PYRROLIDINE-1,2-DICARBOXAMIDES; REFINEMENT;

D O I：

10.1016/j.bmcl.2010.06.126

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of (3R,4R)-pyrrolidine-3,4-dicarboxylic acid amides was investigated with respect to their factor Xa inhibitory activity, selectivity, pharmacokinetic properties, and ex vivo antithrombotic activity. The clinical candidate from this series, R1663, exhibits excellent selectivity against a panel of serine proteases and good pharmacokinetic properties in rats and monkeys. A Phase I clinical study with R1663 has been finalized. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：5313 / 5319

页数：7

共 40 条

[1] THE CCP4 SUITE - PROGRAMS FOR PROTEIN CRYSTALLOGRAPHY [J].

BAILEY, S .

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1994, 50 :760-763

[2] Apixaban [J].

Bates, S. M. ;

Weitz, J. I. .

DRUGS OF THE FUTURE, 2008, 33 (04) :293-301

[3] Refinement of severely incomplete structures with maximum likelihood in BUSTER-TNT [J].

Blanc, E ;

Roversi, P ;

Vonrhein, C ;

Flensburg, C ;

Lea, SM ;

Bricogne, G .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2004, 60 :2210-2221

[4]

Blondon M, 2009, EXPERT OPIN PHARMACO, V10, P1159, DOI [10.1517/14656560902911470, 10.1517/14656560902911470 ]

[5] Bayesian statistical viewpoint on structure determination: Basic concepts and examples [J].

Bricogne, G .

MACROMOLECULAR CRYSTALLOGRAPHY, PT A, 1997, 276 :361-423

[6] DIRECT PHASE DETERMINATION BY ENTROPY MAXIMIZATION AND LIKELIHOOD RANKING - STATUS-REPORT AND PERSPECTIVES [J].

BRICOGNE, G .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 1993, 49 :37-60

[7] Crystallography & NMR system:: A new software suite for macromolecular structure determination [J].

Brunger, AT ;

Adams, PD ;

Clore, GM ;

DeLano, WL ;

Gros, P ;

Grosse-Kunstleve, RW ;

Jiang, JS ;

Kuszewski, J ;

Nilges, M ;

Pannu, NS ;

Read, RJ ;

Rice, LM ;

Simonson, T ;

Warren, GL .

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1998, 54 :905-921

[8] Novel factor Xa inhibitors: a patent review [J].

de Candia, Modesto ;

Lopopolo, Gianfranco ;

Altomare, Cosimo .

EXPERT OPINION ON THERAPEUTIC PATENTS, 2009, 19 (11) :1535-1580

[9] Coot:: model-building tools for molecular graphics [J].

Emsley, P ;

Cowtan, K .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2004, 60 :2126-2132

[10] A dose escalation study of YM150, an oral direct factor Xa inhibitor, in the prevention of venous thromboembolism in elective primary hip replacement surgery [J].

Eriksson, B. I. ;

Turpie, A. G. G. ;

Lassen, M. R. ;

Prins, M. H. ;

Agnelli, G. ;

Kalebo, P. ;

Gaillard, M. L. ;

Meems, L. .

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2007, 5 (08) :1660-1665

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