CVS-1123, A Direct Thrombin Inhibitor, Prevents Occlusive Arterial and Venous Thrombosis in a Canine Model of Vascular Injury

Rebello, Sam; Miller, Bernard V.; Basler, Geoffrey C.; Lucchesi, Benedict R.

doi:10.1097/00005344-199702000-00013

Cited by 24 publications

(13 citation statements)

References 36 publications

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“…The primate model of thrombosis used in this study is based on and adapted from a similar model in dogs in which electrolytic injury is used to induce thrombosis in a carotid artery (Rote et al, 1994;Toombs et al, 1995;Rebello et al, 1997). A number of antithrombotic and antiplatelet compounds have been studied and shown to be effective in this model, including direct and indirect thrombin inhibitors (Sudo and Lucchesi, 1996;Rebello et al, 1997) and platelet GPIIb/IIIa antagonists (Rote et al, 1994;Sudo et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…A number of antithrombotic and antiplatelet compounds have been studied and shown to be effective in this model, including direct and indirect thrombin inhibitors (Sudo and Lucchesi, 1996;Rebello et al, 1997) and platelet GPIIb/IIIa antagonists (Rote et al, 1994;Sudo et al, 1995). Thus, the model in the dog seems to be both platelet-and thrombin-dependent.…”

Section: Discussionmentioning

confidence: 99%

“…We used an electrolytic injury-induced model of thrombosis in primates based on modifications to a similar model in dogs (Rote et al, 1994;Rebello et al, 1997). Ten cynomolgus monkeys of either sex, weighing 3 to 6 kg, were used in this study.…”

Section: Methodsmentioning

confidence: 99%

“…We used an experimental model of thrombosis involving electrolytic injury to the carotid arteries and subsequent thrombus formation, as assessed by absence of blood flow. The model was based on a modification of a similar model in dogs (Rote et al, 1994;Rebello et al, 1997). After intravenous infusion of RWJ-58259 or vehicle, the degree of vessel stenosis induced by electrolytic injury to each carotid artery independently was characterized by the incidence of occlusion and time to occlusion.…”

Section: Expression Of Pars In Platelets Of Cynomolgus Monkeysmentioning

confidence: 99%

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Blockade of the Thrombin Receptor Protease-Activated Receptor-1 with a Small-Molecule Antagonist Prevents Thrombus Formation and Vascular Occlusion in Nonhuman Primates

Derian¹,

Damiano²,

Addo³

et al. 2003

J Pharmacol Exp Ther

155

127

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Although it is well recognized that human platelet responses to ␣-thrombin are mediated by the protease-activated receptors PAR-1 and PAR-4, their role and relative importance in plateletdependent human disease has not yet been elucidated. Because the expression profile of PARs in platelets from nonprimates differs from humans, we used cynomolgus monkeys to evaluate the role of PAR-1 in thrombosis. Based on reverse transcription-polymerase chain reaction, PAR expression in platelets from cynomolgus monkeys consisted primarily of PAR-1 and PAR-4, thereby mirroring the profile of human platelets. We probed the role of PAR-1 in a primate model of vascular injury-induced thrombosis with the selective PAR-1 antagonist (␣S)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Expression Of Pars In Platelets Of Cynomolgus Monkeysmentioning

confidence: 99%

See 2 more Smart Citations

Blockade of the Thrombin Receptor Protease-Activated Receptor-1 with a Small-Molecule Antagonist Prevents Thrombus Formation and Vascular Occlusion in Nonhuman Primates

Derian¹,

Damiano²,

Addo³

et al. 2003

J Pharmacol Exp Ther

155

127

View full text Add to dashboard Cite

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“…There have been some reports of orally active thrombin inhibitors, which are efficacious in animal models of thrombosis, but the compounds need to be optimized and their oral bioavailability and pharmacokinetic properties improved [5][6][7][8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic properties of TDP4815 after single intravenous and oral administrations to rat, rabbit, monkey, dog and in vitro drug metabolism

Chen

Cheng

Tio³

et al. 2008

Biopharm & Drug Disp

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The pharmacokinetics of TDP4815 was evaluated in rats, rabbits, dogs and monkeys. After intravenous administration, TDP4815 achieved C(O) of 3255 ng/ml in rats at 5 mg/kg, 9066 ng/ml in rabbits and 7858 ng/ml in monkeys at 6 mg/kg, and 4457 ng/ml in dogs at 3 mg/kg. The clearance (C(L)) was 3105, 1692, 835 and 640 ml/h/kg in rats, rabbits, monkeys and dogs, respectively. The volume of distribution (V(Z)) was more than 3861 ml/kg in all species, except 1915 ml/kg in monkeys. The oral bioavailability was rabbit >rat> monkey compared at 100 mg/kg, but it was much higher in dogs (>64%) after oral administrations. The calculated intrinsic clearance data suggested that the clearance of dog and human was restricted by binding to the plasma protein, and the clearance of rat and monkey was dependent on both the free fraction of plasma protein binding and the liver blood flow rate. The unbound hepatic intrinsic clearance of monkey was close to its C(L) suggesting that the hepatic clearance was an important excretion in monkeys. The poor oral bioavailability in the monkey may be related to the extensive glucuronidation. The V(Z).kg and C(L).kg in test species showed good correlation with the animal body weights (R(2)=0.87 and 0.96).

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Backbone amide linker (BAL) strategy forNα-9-fluorenylmethoxycarbonyl (Fmoc) solid-phase synthesis of peptide aldehydes

Kappel

Bárány

2005

J. Peptide Sci.

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A rapid and efficient strategy has been developed for the general synthesis of complex peptide aldehydes. N(alpha)-Benzyloxycarbonylamino acids were converted to protected aldehyde building blocks for solid-phase synthesis in four steps and moderate overall yields. The aldehydes were protected as 1,3-dioxolanes except for one case where a dimethyl acetal was used. These protected amino aldehyde monomers were then incorporated onto 5-[(2 or 4)-formyl-3,5-dimethoxyphenoxy]butyryl-resin (BAL-PEG-PS) by reductive amination, following which the penultimate residue was introduced by HATU-mediated acylation. The resultant resin-bound dipeptide unit, anchored by a backbone amide linkage (BAL), was extended further by routine Fmoc chemistry procedures. Several model peptide aldehydes were prepared in good yields and purities. Some epimerization of the C-terminal residue occurred (10% to 25%), due to the intrinsic stereolability conferred by the aldehyde functional group, rather than any drawbacks to the synthesis procedure.

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CVS-1123, A Direct Thrombin Inhibitor, Prevents Occlusive Arterial and Venous Thrombosis in a Canine Model of Vascular Injury

Cited by 24 publications

References 36 publications

Blockade of the Thrombin Receptor Protease-Activated Receptor-1 with a Small-Molecule Antagonist Prevents Thrombus Formation and Vascular Occlusion in Nonhuman Primates

Blockade of the Thrombin Receptor Protease-Activated Receptor-1 with a Small-Molecule Antagonist Prevents Thrombus Formation and Vascular Occlusion in Nonhuman Primates

Pharmacokinetic properties of TDP4815 after single intravenous and oral administrations to rat, rabbit, monkey, dog and in vitro drug metabolism

Backbone amide linker (BAL) strategy forNα-9-fluorenylmethoxycarbonyl (Fmoc) solid-phase synthesis of peptide aldehydes

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