High-throughput synthesis and optimization of thrombin inhibitors via urazole α-addition and Michael addition

Boatman, P. Douglas; Urban, Ján; Nguyen, Minh Khanh; Qabar, Maher; Kahn, Michaël

doi:10.1016/s0960-894x(03)00155-0

Cited by 36 publications

(18 citation statements)

References 11 publications

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“…Employing the same strategy, Boatman and co-workers carried out a high-throughput synthesis of thrombin inhibitors. 51 Similarly, in 2003, Taran and co-workers utilized this methodology to obtain acrylate derivatives via a-addition reaction of pyridones to alkynoates. 52 The synthesized acrylates were successfully applied to prepare a large number of multidentate metal ligands.…”

Section: Nucleophilic Addition To the A-position Of Activated Alkynesmentioning

confidence: 99%

Organocatalytic transformations of alkynals, alkynones, propriolates, and related electron-deficient alkynes

et al. 2014

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Section: Nucleophilic Addition To the A-position Of Activated Alkynesmentioning

confidence: 99%

Organocatalytic transformations of alkynals, alkynones, propriolates, and related electron-deficient alkynes

et al. 2014

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“…This approach enabled a number of structurally-diverse BOX derivatives of the type (184) to be synthesized and evaluated for serine protease activity [241]. Boatman and co-workers at Molecumetics have disclosed the synthesis of potent thrombin inhibitors based on a triazolopyridazine scaffold [234]. Key elements of the synthesis include a hetero Diels-Alder reaction between a resin-bound diene and an oxidized urazole, α-addition of the urazole cycloadduct to propiolate, and conjugate addition with a variety of nucleophiles.…”

Section: Serine Proteasesmentioning

confidence: 99%

Design and Synthesis of Protein Superfamily-Targeted Chemical Libraries for Lead Identification and Optimization

Shuttleworth¹,

Connors²,

Fu³

et al. 2005

CMC

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This review chronicles original literature dating back to 1992 outlining the applications of parallel synthesis and combinatorial chemistry to the synthesis of compound libraries focused towards specific superfamilies of molecular targets. Target families that have received significant literature coverage include kinases, proteases, nuclear hormone receptors and cell surface receptors, notably GPCRs.

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“…The compounds 121 (K i = 23 pM), 122 (K i = 11 nM), and 123 (K i = 16 pM) are potent thrombin inhibitors and selective towards trypsin (K i > 40 nM), however, no pharmacokinetic data was given [162,163]. developed by C&C Research Laboratories, an oral bioavailability of 10.6% in rats was found.…”

Section: Inhibitors Of Other Structural Typementioning

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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High-throughput synthesis and optimization of thrombin inhibitors via urazole α-addition and Michael addition

Cited by 36 publications

References 11 publications

Organocatalytic transformations of alkynals, alkynones, propriolates, and related electron-deficient alkynes

Organocatalytic transformations of alkynals, alkynones, propriolates, and related electron-deficient alkynes

Design and Synthesis of Protein Superfamily-Targeted Chemical Libraries for Lead Identification and Optimization

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

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