Design, Synthesis, and Evolution of a Novel, Selective, and Orally Bioavailable Class of Thrombin Inhibitors:  P1-Argininal Derivatives Incorporating P3-P4 Lactam Sulfonamide Moieties

Je, Semple; Rowley, David C.; Tk, Brunck; Ha‐Uong, Theresa; Nk, Minami; Td, Owens; Sy, Tamura; Ea, Goldman; Dv, Siev; Rj, Ardecky; Sh, Carpenter; Ge, Yao; Bm, Richard; Tg, Nolan; Håkanson, K; Tulinsky, A.; Rf, Nutt; Wc, Ripka

doi:10.1021/jm960572n

Cited by 64 publications

(10 citation statements)

References 31 publications

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“…For instance, in the case of hydrogenolysis, partial hydrogenation of Trp or even Phe can occur. 308 Due to the clean removal of the nitro group by hydrogenolysis and its low cost, nitro protection is still used for large-scale solution synthesis of peptides 309,310 and even for SPS, where the nitro group is removed by hydrogenolysis after the cleavage from the resin. 311 Create PDF files without this message by purchasing novaPDF printer (http://www.novapdf.com) …”

Section: Protecting Groups Removed By Acidmentioning

confidence: 99%

Amino Acid-Protecting Groups

2009

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Section: Protecting Groups Removed By Acidmentioning

confidence: 99%

Amino Acid-Protecting Groups

2009

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“…Due to the enormous potential in preventing cardiovascular diseases, thrombin inhibitors have been one of the hottest topics in drug discovery in recent years. Sample et al were the first to introduce the Freidinger lactam methodology to thrombin inhibitor design, applying similar strategy as in the case of ACE inhibitors [56].…”

Section: Thrombin Inhibitorsmentioning

confidence: 99%

“…In order to overcome this disadvantage and improve thrombin binding affinity, increasing conformational rigidity of the peptide backbone of 56 was undertaken, as highlighted in Scheme 12. The resulting 6-membered Freidinger lactams 57 were found to be potent thrombin inhibitors due to the fact that the lactam carbonyl moiety of 58, along with theamide NH group, provides the essential hydrogen bond acceptor and donor elements necessary for antiparallelhydrogen bonding with the Gly 216 residue in the thrombin active site [56].…”

Section: Thrombin Inhibitorsmentioning

confidence: 99%

The Application of Freidinger Lactams and their Analogs in the Design of Conformationally Constrained Peptidomimetics

Perdih¹,

Kikelj

2006

CMC

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Peptides exist in solution as an equilibrium mixture of conformers. The backbone conformational constraints are of interest as a means of limiting degrees of freedom and thereby constraining a synthetic peptide into the bioactive conformation. This concept plays an important role in the design of peptidomimetics in the drug development process. In the early eighties, Freidinger proposed the concept of protected lactam-bridged dipeptides, which was a milestone in the design of conformationally constrained peptides. These types of compounds, now widely known as Freidinger lactams, have been of interest to many medicinal and peptide chemists. This review seeks to present the various applications that Freidinger lactams and their hetero-, fused- and unsaturated analogs have found in the design of conformationally constrained peptidomimetics in different therapeutic areas.

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“…Incorporation of sulphonamide containing lactam structures as P4-P2 mimetic alone (26, K i = 0.54 nM) or in combination with P1 amidinopiperidine-derived aldehydes (27, IC 50 = 0.57 nM) considerably improved trypsin selectivity. [57][58][59]. Unfortunately, a lower oral bioavailability was found for the amidinopiperidine (27) constants > 10 7 M -1 s -1 were highly potent in a thrombosis model in baboons [63].…”

Section: Electrophilic Inhibitorsmentioning

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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Design, Synthesis, and Evolution of a Novel, Selective, and Orally Bioavailable Class of Thrombin Inhibitors: P1-Argininal Derivatives Incorporating P3-P4 Lactam Sulfonamide Moieties

Cited by 64 publications

References 31 publications

Amino Acid-Protecting Groups

Amino Acid-Protecting Groups

The Application of Freidinger Lactams and their Analogs in the Design of Conformationally Constrained Peptidomimetics

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

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