Benzylamine-based selective and orally bioavailable inhibitors of thrombin

Lee, Koo; Jung, Won-Hyuk; Park, Cheol Won; Hong, Chang Yee; Kim, In Chul; Kim, Sang Soo; Oh, Yeong Soo; Kwon, Oh-Seok; Lee, Sung-Hack; Park, Hee Dong; Kim, Sang Woong; Lee, Yong Hee; Yoo, Yung Joon

doi:10.1016/s0960-894x(98)00456-9

Cited by 28 publications

(17 citation statements)

References 15 publications

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“…65 Further optimization of P3 in the foresaid inhibitors gave 25 (Ki ¼ 18.3 nM). 66 Efforts to further enhance the thrombin inhibitory potency of this series by replacing the naphthyl moiety of the sulfonamide with a more hydrophobic gave 26 (Ki ¼ 0.045 nM). 67 The Novartis group 68,69 optimized 13 to develop 27 (CGH 1668, Ki ¼ 39 nM).…”

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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“…However, the phase I clinical study of 85 revealed less than desired anticoagulant activity and shorter duration of action, and thus, its further development is limited [86]. The same group developed similar compounds containing an amidinothienylalanine (87, K i = 0.6 nM), the less basic p-aminomethylphenylalanine (88, K i = 6.6 nM, pKa = 9.35, F = 77 % in rats), or a nearly neutral substituted propargylglycin amide at P1 position (89, K i = 5 nM) [126][127][128]. trypsin-like serine proteases of the clotting cascade and the fibrinolytic enzymes with inhibition constants > 50 µM and shows only a moderate chymotrypsin affinity (K i = 0.58 µM) [129].…”

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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“…46 Further optimization of the sulfonamide substituent gave compound 12 which was orally active in rats ). 47 The strategy of incorporating less basic P1 groups to improve the oral activity of argatroban analogs was also pursued by groups at Bristol-Myers Squibb. 48,49 It was found that 2-aminopyridine derivative 13 was roughly equipotent to its parent arginine derivative 14 and that this change significantly increased the permeability of the compound across a Caco-2 cell monolayer.…”

Section: A Thrombin Inhibitors Originating From Tamementioning

confidence: 99%

Small, noncovalent serine protease inhibitors

Sanderson

1999

Med. Res. Rev.

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Benzylamine-based selective and orally bioavailable inhibitors of thrombin

Cited by 28 publications

References 15 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

Small, noncovalent serine protease inhibitors

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