Structure-based design of novel groups for use in the P1 position of thrombin inhibitor scaffolds. Part 1: Weakly basic azoles

Isaacs, Richard C.A.; Solinsky, M.G; Cutrona, Kellie J.; Newton, Christina L.; Naylor-Olsen, Adel M.; Krueger, Julie A.; Lewis, Sidney D.; Lucas, Bobby J.

doi:10.1016/j.bmcl.2005.09.083

Cited by 14 publications

(13 citation statements)

References 14 publications

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“…The strong basicity of such groups, however, often causes low oral bioavailability due to poor intestinal absorption. In addition, some inhibitors with aminocyclohexane P1s display in vivo toxicity, the severity of which is a direct function of the p K a of the aminocyclohexane . To address these problems, we have previously reported on a series of thrombin inhibitors exhibiting a novel oxyguanidine moiety, which serves as an arginine surrogate of the arginine-glycine-aspartic acid (RGD) type thrombin inhibitors .…”

Section: Resultsmentioning

confidence: 99%

“…A lead compound, featuring an 2-amino-6-methyl pyridine at P1, had a K i of 0.8 nM for thrombin and 1800 nM for trypsin. Other P1 groups have also been employed as follows: imidazopyridazines, 5-linked indoles, and azaindoles (the affinity of the three isomers correlates with the acidity of the conjugate acid), azoles, imidazole acetamides, and aminopyridines …”

Section: Resultsmentioning

confidence: 99%

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Discovery and Clinical Evaluation of 1-{N-[2-(Amidinoaminooxy)ethyl]amino}carbonylmethyl-6-methyl-3-[2,2-difluoro-2-phenylethylamino]pyrazinone (RWJ-671818), a Thrombin Inhibitor with an Oxyguanidine P1 Motif

Markotan

Ballentine

et al. 2010

J. Med. Chem.

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We have identified RWJ-671818 (8) as a novel, low molecular weight, orally active inhibitor of human alpha-thrombin (K(i) = 1.3 nM) that is potentially useful for the acute and chronic treatment of venous and arterial thrombosis. In a rat deep venous thrombosis model used to assess antithrombotic efficacy, oral administration of 8 at 30 and 50 mg/kg reduced thrombus weight by 87 and 94%, respectively. In an anesthetized rat antithrombotic model, where electrical stimulation of the carotid artery created a thrombus, 8 prolonged occlusion time 2- and 3-fold at 0.1 and 1.0 mg/kg, i.v., respectively, and more than doubled activated clotting time and activated partial thromboplastin time at the higher dose. This compound had excellent oral bioavailability of 100% in dogs with an estimated half-life of approximately 3 h. On the basis of its noteworthy preclinical data, 8 was advanced into human clinical trials and successfully progressed through phase 1 studies.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Discovery and Clinical Evaluation of 1-{N-[2-(Amidinoaminooxy)ethyl]amino}carbonylmethyl-6-methyl-3-[2,2-difluoro-2-phenylethylamino]pyrazinone (RWJ-671818), a Thrombin Inhibitor with an Oxyguanidine P1 Motif

Markotan

Ballentine

et al. 2010

J. Med. Chem.

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“…Typically, DTIs possess a P1 group that fills the specific S1 pocket. Generally, to produce potent inhibitors, the P1 ligand features a strongly basic functional group such as guanidine (argatroban), alkylamine, amidine, benzamidine (dabigatran), or 4-aminopyridine (26). Patents WO00/42059 (27), US2007/0249578 A1 (28) and US2010/0087651 Al (29) disclosed a series of compounds in which the P1 position was replaced with amidino, benzamidine, or their analogs.…”

Section: The Development Of Direct Thrombin Inhibitorsmentioning

confidence: 99%

“…The inhibition constant (Ki) values for thrombin and trypsin are 0.59 and 32.23 µM, respectively, for this compound. Azoles (26,33) (such as imidazoles, aminothiazoles and N-acetamidoimidazole) and aryl heterocycles (pyridines, pyrazinones, piperidines and pyridinones) are also weakly basic groups. When they are incorporated into the P1 position, the resulting peptides exhibit very good selectivity for thrombin vs. trypsin and lower in vivo toxicity.…”

Section: The Development Of Direct Thrombin Inhibitorsmentioning

confidence: 99%

Direct thrombin inhibitors: Patents 2002–2012 (Review)

Kong

Chen

Wang

et al. 2014

Molecular Medicine Reports

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Acute vascular diseases and other thromboses of the blood system constitute major health risks in developing countries. Thrombin plays a central role in blood coagulation, which is a crucial process involved in thrombosis. Direct thrombin inhibitors (DTIs) such as argatroban, dabigatran, dabigatran etexilate, lepirudin, desirudin and bivalirudin, which bind to thrombin and block its enzymatic activity, are widely and effectively used in the treatment of thromboembolic diseases. DTIs appear to overcome the disadvantages of indirect thrombin inhibitors such as unfractionated heparins (UFH). Although these DTIs show specific advantages over indirect inhibitors, they still present limitations, such as a narrow therapeutic window, and bleeding and anaphylaxis as side-effects. Novel anticoagulant drugs need thus to be developed to overcome these limitations. In the search for additional candidate agents with improved efficacy, safety and high bioavailability in oral administration, a high number of compounds has been identified, such as those derived from the tripeptide template D-Phe-Pro-Arg, aptamers and peptides isolated from blood-sucking animals. These candidates may prove the new agents of choice for the treatment of cardiovascular diseases.

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“…2). A recent report by Isaacs et al [30] on thrombin inhibitors showed that weakly basic imidazoles can function as surrogates for more basic alkylamines. Thioureas bearing an 3-(imidazol-4-yl)propyl group have dramatically reduced basicity in comparison with the -NH 2 group of Lys 9 of SRIF (pKa values of the side chain imidazole is about 7, whereas the -NH 2 group of Lys is about 10.5).…”

Section: Nonpeptide Ligands At Sstmentioning

confidence: 99%