Interaction of peptidyl arginine aldehydes with thrombin

Bajusz, S.; Széll, E.; Horváth, Gyula; Barabás, Éva; Bagdy, D

doi:10.1007/978-94-011-3034-9_323

Cited by 9 publications

(9 citation statements)

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“…It is very low in the case of papain and trypsin but significant for thrombin, which is probably due to the high thrombin-affinity of 6; D-Phe-Pro-Agm, a similar structure without C-terminal serine trap, also shows rather high activity. 37 As a consequence, the L␣ : L␤ potency ratios calculated for papain are high, similar to that obtained for trypsin.…”

Section: Inhibition Of Caspases By Peptidyl Aspartals and ␤-Homo-aspasupporting

confidence: 65%

Peptidyl ?-homo-aspartals (3-amino-4-carboxybutyraldehydes): New specific inhibitors of caspases

Bajusz¹,

Fauszt²,

Németh³

et al. 1999

Biopolymers

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Section: Inhibition Of Caspases By Peptidyl Aspartals and ␤-Homo-aspasupporting

confidence: 65%

Peptidyl ?-homo-aspartals (3-amino-4-carboxybutyraldehydes): New specific inhibitors of caspases

Bajusz¹,

Fauszt²,

Németh³

et al. 1999

Biopolymers

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“…Polypeptidstrukturen ermöglichen zwar viele Interaktionen mit Thrombin und ergeben so potente Inhibitoren; da aber nur Inhibitoren mit kleinen Molekülmassen (<500 g mol −1 ) die Chance haben, das gastrointestinale Epithel zu passieren und in die Blutbahn zu gelangen, wurden die 1982 von Bajusz et al. offengelegten Dipeptidstrukturen wie D ‐Phe‐Pro‐Agmatin ( 5 ),16 obwohl nur schwach wirksam, zum wichtigen Startpunkt weiterer Forschungsarbeiten (Schema ). AstraZeneca verfolgte als erste erfolgreich diesen Dipeptidansatz und entwickelte ausgehend von 5 den klinischen Kandidaten Inogatran ( 6 ) mit über 100‐mal höherer In‐vitro‐Potenz, der allerdings eine nur unzureichende Bioverfügbarkeit aufweist und relativ schnell ausgeschieden wird.…”

Section: Thrombin‐inhibitorenunclassified

Theoretical Investigation of the Photochemical C²–C⁶ Cyclisation of Enyne–Heteroallenes

Spöler¹,

Engels²

2003

Chemistry A European J

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Herein we discuss computations that explain experimental results regarding a highly efficient triplet analogue of the C(2)-C(6) cyclisation of enyne-heteroallenes recently discovered by Schmittel and co-workers.1 To shed some light on the reasons for the differences found between enyne-carbodiimides, enyne-ketenimines and enyne-allenes, we have computed the reaction profiles of the C(2)-C(6) and of the C(2)-C(7) cyclisations for various model compounds, assuming that the reactions take place on the lowest-lying triplet surfaces. Our results nicely explain the differences and the unexpected high efficiency found for the enyne-carbodiimides. The differences between enyne-carbodiimides and enyne-ketenimines prove to be due to differences in the shapes of the corresponding triplet surfaces. In contrast to the enyne-carbodiimides, for which our calculations predict that a direct cyclisation to the biradical intermediates should occur after the vertical excitation, the enyne-ketenimines relax into a local minimum on the triplet surface. As a consequence, further reaction channels are opened. Our computations indicate that enyne-allene compounds do not react because the necessary excitation energy lies outside the range of the employed triplet photosensitizer. Finally, the close agreement between our results and the experimental findings indicates that the underlying reasons for the differences in the photochemical behaviour of enyne-carbodiimides, enyne-ketenimines and enyne-allenes are related to differences in the electronic structures of the parent systems, while substituent effects are less important.

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“…In addition to the electrophilic inhibitors of the DPhePro-Arg-type Bajusz et al published a first non-electrophilic derivative with a C-terminal agmatine, a decarboxylated derivative of arginine [43]. This compound (16, K i = 0.18 µM) was not further developed at that time, because it was significantly less potent than the analog aldehydes (3,4).…”

Section: Non-electrophilic Inhibitorsmentioning

confidence: 92%

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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Interaction of peptidyl arginine aldehydes with thrombin

Cited by 9 publications

References 1 publication

Peptidyl ?-homo-aspartals (3-amino-4-carboxybutyraldehydes): New specific inhibitors of caspases

Peptidyl ?-homo-aspartals (3-amino-4-carboxybutyraldehydes): New specific inhibitors of caspases

Theoretical Investigation of the Photochemical C²–C⁶ Cyclisation of Enyne–Heteroallenes

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

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Interaction of peptidyl arginine aldehydes with thrombin

Cited by 9 publications

References 1 publication

Peptidyl ?-homo-aspartals (3-amino-4-carboxybutyraldehydes): New specific inhibitors of caspases

Peptidyl ?-homo-aspartals (3-amino-4-carboxybutyraldehydes): New specific inhibitors of caspases

Theoretical Investigation of the Photochemical C2–C6 Cyclisation of Enyne–Heteroallenes

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

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Theoretical Investigation of the Photochemical C²–C⁶ Cyclisation of Enyne–Heteroallenes