Multicenter, dose-ranging study of efegatran sulfate versus heparin with thrombolysis for acute myocardial infarction: The Promotion of Reperfusion in Myocardial Infarction Evolution (PRIME) trial

Bengtson, James R.; Adolphson, Mary; Brewer, David L.; Jacobs, David R.; Gard, J. L.; Cahoon, L.; Bloom, Michelle E.; Kennelly, Brian M.; Porter, Kyle; Kmonicek, J.; Krainin, Fred; Shane, J. R.; Marquis, Jean-François; Kearns, Sharon Ann; Moliterno, David J.; DeSantis, Pascual; Ohman, E. Magnus; Martz, Colin A.; Brown, David L.; Bulley, Margaret; Worley, Seth J.; Slovak, Jennifer E.; Hollywood, L.; Knepper, K; Browne, Kevin F.; Telatnik, Mary; Frey, Martin J.; Browning, Travis; French, William J.; Wang, S.; Kleiman, Neal S.; Baysinger, L.; Edwards, Anthony; Barbeau, Gérald; Lariviere, M. M.; Hermiller, James; Diel, S.; Wilson, Jenny; Friedewald, A.; Tenaglia, Alan N.; Bozeman, R.; Roper, William L.; Grossman, William; Fletcher, Kate; Andersen, Robyn; Spriggs, Douglas; Wahl, Simone; Talley, J. David; Boyles, M.; Almond, David; White, James A.; Adelman, Allan G.; Foulger, V.; Webber, Steve; Kells, Catherine; Fawcett, Tonks N; Butler, J. L.; Scrivner, J.; Miller, Michael J.; Owens, B.; Corder, Clinton N.; Clinton, Cassie; Johnson, J. Cale; Myrna, M.; Carr, Katelyn A.; Calarco, Joseph S.; Glassman, Jerrold; Stein, Andreas; Marsh, David; Penny, Barbara; Small, David S.; Goodman, Dennis; D, Walston; Koren, Michael; Teeter, Kjersten; Hudson, Michael

doi:10.1067/mhj.2002.119896

Cited by 17 publications

(1 citation statement)

References 19 publications

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“…As described above for the chloromethyl ketones, these arginal-derived inhibitors serve as excellent biochemical tools, but they are rather unsuited for therapeutic development. Although few peptidic serine protease inhibitors with a C-terminal arginal residue, like the thrombin inhibitors CVS-1123 and efegatran, reached preclinical and clinical development, their development was discontinued mainly for two reasons: the compounds revealed limited selectivities due to their nonspecific serine trap and suffered from an insufficient antithrombotic potential compared to other direct thrombin inhibitors. The latter drawback might be partially explained by studies with the related protease inhibitor leupeptin (acetyl-Leu-Leu-Arg-H), which exists in solution mainly in its cyclized hemiaminal form (56%) and as a hydrate (42%), whereas only 2% of the inhibitory active aldehyde form was detected.…”

Section: Synthetic Active Site-directed Inhibitorsmentioning

confidence: 99%

Fibrinolysis Inhibitors: Potential Drugs for the Treatment and Prevention of Bleeding

et al. 2019

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Hyperfibrinolytic situations can lead to lifethreatening bleeding, especially during cardiac surgery. The approved antifibrinolytic agents such as tranexamic acid, εaminocaproic acid, 4-aminomethylbenzoic acid, and aprotinin were developed in the 1960s without the structural insight of their respective targets. Crystal structures of the main antifibrinolytic targets, the lysine binding sites on plasminogen's kringle domains, and plasmin's serine protease domain greatly contributed to the structure-based drug design of novel inhibitor classes. Two series of ligands targeting the lysine binding sites have been recently described, which are more potent than the most-widely used antifibrinolytic agent, tranexamic acid. Furthermore, four types of promising active site inhibitors of plasmin have been developed: tranexamic acid conjugates targeting the S1 pocket and primed sites, substrate-analogue linear homopiperidylalanine-containing 4amidinobenzylamide derivatives, macrocyclic inhibitors addressing nonprimed binding regions, and bicyclic 14-mer SFTI-1 analogues blocking both, primed and nonprimed binding sites of plasmin. Furthermore, several allosteric plasmin inhibitors based on heparin mimetics have been developed.

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Section: Synthetic Active Site-directed Inhibitorsmentioning

confidence: 99%

Fibrinolysis Inhibitors: Potential Drugs for the Treatment and Prevention of Bleeding

et al. 2019

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Covalent Enzyme Inhibition in Drug Discovery and Development

Mehdi

2013

Enzyme Technologies

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Mapping ischemic risk region and necrosis in the isolated heart using EPR imaging

Murugesan

Kuppusamy

et al. 2003

Magnetic Resonance in Med

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Reperfusion of ischemic tissue is a common event in the treatment of heart attack and stroke. To study disease pathogenesis, methods are required to measure tissue perfusion and area at risk, as well as localized regions of injury. While histology can provide this information, its destructive nature precludes assessment of time course. Thus, there is a critical need for a noninvasive technique to obtain this information. To map myocardial redox state as a possible index of cellular ischemia and viability, electron paramagnetic resonance (EPR) imaging experiments were performed on isolated rat hearts before and after the onset of regional ischemia using nitroxide spin labels. With coronary artery occlusion, the EPR images clearly showed the risk region as a void of lower intensity that reversed upon reperfusion. The extent of risk region in the heart was similar in EPR imaging and histological measurements. The unique information obtained regarding the time course of changes in redox metabolism of the risk region and normal myocardium can provide important insights regarding the mechanisms of myocardial injury during and following ischemia.

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Multicenter, dose-ranging study of efegatran sulfate versus heparin with thrombolysis for acute myocardial infarction: The Promotion of Reperfusion in Myocardial Infarction Evolution (PRIME) trial

Cited by 17 publications

References 19 publications

Fibrinolysis Inhibitors: Potential Drugs for the Treatment and Prevention of Bleeding

Fibrinolysis Inhibitors: Potential Drugs for the Treatment and Prevention of Bleeding

Covalent Enzyme Inhibition in Drug Discovery and Development

Mapping ischemic risk region and necrosis in the isolated heart using EPR imaging

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