the design and synthesis of thrombin inhibitors: the introduction of in vivo efficacy and oral bioavailability into benzthiazolylalanine inhibitors

Hayler, Judy; Kane, Peter D.; LeGrand, Darren; Lugrin, Florence; Menear, Keith; Price, Richard; Allen, Mark S.; Cockcroft, Xiaoling; Ambler, J. E.; Butler, K.D.; Dunnet, Karren; Mitchelson, Andrew; Talbot, Mark; Tweed, Morris; Wills, Nicholas

doi:10.1016/s0960-894x(00)00283-3

Cited by 10 publications

(2 citation statements)

References 8 publications

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“…Though active site S1 has Asp 189 to form salt bridge interactions, it is also highly lipophilic because of presence of Ala 190 . 56 Therefore, mono and bicyclic lipophilic groups at P1 were incorporated to obtain the most potent compound 16 (CGH 752, Ki ¼ 0.026 nM) to bind to S1 pocket.…”

Section: B Reversible Covalent Thrombin Inhibitorsmentioning

confidence: 99%

Progress in the design of low molecular weight thrombin inhibitors

2005

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Intravascular thrombosis and its complication, embolism, is a leading cause of morbidity and mortality throughout the world. Past few decades have seen a great deal of progress in the development of antithrombotic agents, though the current treatment options are limited to heparin, LMW heparins, and warfarin. Detailed understanding of the biochemical and biophysical mechanisms of activation and regulation of blood coagulation have helped in developing specific inhibitors of enzymes, especially thrombin, within the coagulation cascade. Thrombin plays a central role in the coagulation cascade and so has become the primary target for the development of antithrombotic drugs. The review covers the main pharmacological aspects of haemostasis and thrombosis and provides an update on low molecular weight thrombin inhibitors along with the limitations of the prevalent antithrombotic agents. Recent developments in small molecule inhibitors of Protease Activated Receptor-1 (PAR-1) which can be helpful for the treatment of thrombotic and vascular proliferative disorders, have also been discussed.

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Section: B Reversible Covalent Thrombin Inhibitorsmentioning

confidence: 99%

Progress in the design of low molecular weight thrombin inhibitors

2005

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“…The most favorable overall profile was found for 93 (K i = 57 nM, CGH1484), which contains a solubilising piperazine ring combined with a morpholine substituent. Surprisingly, this compound has an oral bioavailability of 28 % when dosed to rats, despite its relatively high molecular weight of approximately 825 Da [133].…”

Section: Secondary Amides Of Arginine and Arginine Surrogatesmentioning

confidence: 99%

Progress in the Development of Synthetic Thrombin Inhibitors as New Orally Active Anticoagulants

Steinmetzer

Stürzebecher²

2004

CMC

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The trypsin-like serine protease thrombin is a multifunctional key enzyme at the final step of the coagulation cascade and is involved in the regulation of hemostasis and thrombosis. An increased activation of coagulation can result in severe thromboembolic disorders, one of the major reasons responsible for mortality and morbidity in western world. Therefore, an effective, safe, and orally available thrombin inhibitor could be a useful anticoagulant drug for the daily prophylaxis of venous and arterial thrombosis and prevention of myocardial infarction for high-risk patients. Synthetic thrombin inhibitors have a long history; initial compounds were derived from electrophilic ketone- and aldehyde-analogs of arginine. First potent leads of non-covalent inhibitors were developed in the early eighties, which were further optimised in the nineties, after the X-ray structure of thrombin became available. In the meantime a huge number of highly active and selective inhibitors has been published, however, only a few of them have an appropriate pharmacokinetic and pharmacodynamic overall profile, which could justify their further development. Very recently, with Ximelagatran a first orally available thrombin inhibitor has been approved in France for the prevention of venous thromboembolic events in major orthopaedic surgery after successful clinical phase III. However, it still has to be awaited, whether the extensive clinical use of Ximelagatran can demonstrate for the first time that direct thrombin inhibitors offer a real benefit in terms of efficacy and safety over established antithrombotic therapies. This review summarizes the current status of synthetic thrombin inhibitors with a focus on more recently published and promising new compounds.

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ChemInform Abstract: Design and Synthesis of Thrombin Inhibitors: The Introduction of in vivo Efficacy and Oral Bioavailability into Benzthiazolylalanine Inhibitors.

Kane¹

2000

ChemInform

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the design and synthesis of thrombin inhibitors: the introduction of in vivo efficacy and oral bioavailability into benzthiazolylalanine inhibitors

Cited by 10 publications

References 8 publications

Progress in the design of low molecular weight thrombin inhibitors

Progress in the design of low molecular weight thrombin inhibitors

Progress in the Development of Synthetic Thrombin Inhibitors as New Orally Active Anticoagulants

ChemInform Abstract: Design and Synthesis of Thrombin Inhibitors: The Introduction of in vivo Efficacy and Oral Bioavailability into Benzthiazolylalanine Inhibitors.

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