34 results on '"STRANIERI, M. T."'
Search Results
2. ChemInform Abstract: Nonpeptide Glycoprotein IIb/IIIa Inhibitors. Part 13. Design and Synthesis of an Orally Active Pyrazolopiperazinone Nonpeptide Fibrinogen Receptor Antagonist.
- Author
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ASKEW, B. C., primary, MCINTYRE, C. J., additional, HUNT, C. A., additional, CLAREMON, D. A., additional, BALDWIN, J. J., additional, ANDERSON, P. S., additional, GOULD, R. J., additional, LYNCH, R. J., additional, CHANG, C. C.-T., additional, COOK, J. J., additional, LYNCH, J. J., additional, HOLAHAN, M. A., additional, SITKO, G. R., additional, and STRANIERI, M. T., additional
- Published
- 2010
- Full Text
- View/download PDF
3. Effects of pentobarbital on pharmacokinetics and pharmacodynamics of a potent fibrinogen receptor antagonist, L-734 217, in dogs
- Author
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Prueksaritanont, T., primary, Stranieri, M. T., additional, Hand, E. L., additional, Ellis, J. D., additional, Holahan, M. A., additional, Sitko, G. R., additional, and Cook, J. J., additional
- Published
- 1997
- Full Text
- View/download PDF
4. ChemInform Abstract: Nonpeptide GPIIb/IIIa Inhibitors. Part 16. Thieno(2,3‐b)thiophene . alpha.‐Sulfonamides are Potent Inhibitors of Platelet Aggregation.
- Author
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PRUGH, J. D., primary, GOULD, R. J., additional, LYNCH, R. J., additional, ZHANG, G., additional, COOK, J. J., additional, HOLAHAN, M. A., additional, STRANIERI, M. T., additional, SITKO, G. R., additional, GAUL, S. L., additional, BEDNAR, R. A., additional, BEDNAR, B., additional, and HARTMAN, G. D., additional
- Published
- 1997
- Full Text
- View/download PDF
5. ChemInform Abstract: Non‐Peptide Glycoprotein IIb/IIIa Antagonists. Part 11. Design and in vivo Evaluation of 3,4‐Dihydro‐1(1H)‐isoquinolinone‐Based Antagonists and Ethyl Ester Prodrugs.
- Author
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HUTCHINSON, J. H., primary, COOK, J. J., additional, BRASHEAR, K. M., additional, BRESLIN, M. J., additional, GLASS, J. D., additional, GOULD, R. J., additional, HALCZENKO, W., additional, HOLAHAN, M. A., additional, LYNCH, R. J., additional, SITKO, G. R., additional, STRANIERI, M. T., additional, and HARTMAN, G. D., additional
- Published
- 1997
- Full Text
- View/download PDF
6. Metabolism-Directed Optimization of 3-Aminopyrazinone Acetamide Thrombin Inhibitors. Development of an Orally Bioavailable Series Containing P1 and P3 Pyridines
- Author
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Burgey, C. S., Robinson, K. A., Lyle, T. A., Sanderson, P. E. J., Lewis, S. D., Lucas, B. J., Krueger, J. A., Singh, R., Miller-Stein, C., White, R. B., Wong, B., Lyle, E., Williams, P. D., Coburn, C. A., Dorsey, B. D., Barrow, J. C., Stranieri, M. T., Holahan, M. A., Sitko, G. R., Cook, J. J., McMasters, D. R., McDonough, C. M., Sanders, W. M., Wallace, A. A., Clayton, F. C., Bohn, D., Leonard, Y. M., Detwiler, T. J., Jr., Lynch, J. J., Jr., Yan, Y., Chen, Z., Kuo, L., Gardell, S. J., Shafer, J. A., and Vacca, J. P.
- Abstract
Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g.,
1 ) which resulted in the modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g.,20 ,24 ,25 ) were identified which exhibit high levels of oral bioavailability and long plasma half-lives.- Published
- 2003
7. Simple high-performance liquid chromatographic method to analyze serum creatinine has several advantages over the Jaffe picric acid reaction as demonstrated with a cimetidine dose response in rhesus monkeys
- Author
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Johns, B. A., Broten, T., Stranieri, M. T., Holahan, M. A., and Cook, J. J.
- Published
- 2001
- Full Text
- View/download PDF
8. Non-Peptide GPIIb/IIIa Inhibitors. 20. Centrally Constrained Thienothiophene α-Sulfonamides Are Potent, Long Acting in Vivo Inhibitors of Platelet Aggregation
- Author
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Egbertson, M. S., Cook, J. J., Bednar, B., Prugh, J. D., Bednar, R. A., Gaul, S. L., Gould, R. J., Hartman, G. D., Homnick, C. F., Holahan, M. A., Libby, L. A., Lynch, J. J., Jr., Lynch, R. J., Sitko, G. R., Stranieri, M. T., and Vassallo, L. M.
- Abstract
The synthesis and pharmacology of
4 , a potent thienothiophene non-peptide fibrinogen receptor antagonist, are reported. Compound4 inhibited the aggregation of human gel-filtered platelets with an IC50 of 8 nM and demonstrated an 8-fold improvement in affinity for isolated GPIIb/IIIa receptors over analogues possessing an isoindolinone backbone. Flow cytometry studies revealed that the binding of4 to resting platelets is a diffusion-controlled process (kon = 3.3 × 106 M-1 s-1) and that4 binds to dog and human platelets with comparable affinity (Kd = 0.04 and 0.07 nM, respectively). Ex vivo platelet aggregation in dogs was completely inhibited by an iv dose of 5 mg/kg, and an oral dose of 50−90 mg/kg followed by low daily doses of 10 mg/kg was sufficient to maintain ~80% inhibition of ex vivo platelet aggregation over several days. Inhibition of ADP-induced platelet aggregation in anesthetized dogs at 77 ± 7% resulted in a moderate 2.5-fold increase in bleeding time, while complete inhibition (100%) resulted in an approximately 10-min bleeding time. Additional doses were required to increase the bleeding time to the maximum time allowed in the protocol (15 min), thus indicating a potentially useful and safe separation of efficacy and bleeding time.- Published
- 1999
9. Efficacious, Orally Bioavailable Thrombin Inhibitors Based on 3-Aminopyridinone or 3-Aminopyrazinone Acetamide Peptidomimetic Templates
- Author
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Sanderson, P. E. J., Lyle, T. A., Cutrona, K. J., Dyer, D. L., Dorsey, B. D., McDonough, C. M., Naylor-Olsen, A. M., Chen, I-W., Chen, Z., Cook, J. J., Cooper, C. M., Gardell, S. J., Hare, T. R., Krueger, J. A., Lewis, S. D., Lin, J. H., Lucas, B. J., Jr., Lyle, E. A., Lynch, J. J., Jr., Stranieri, M. T., Vastag, K., Yan, Y., Shafer, J. A., and Vacca, J. P.
- Abstract
We have addressed the key deficiency of noncovalent pyridinone acetamide thrombin inhibitor L-374,087 (
1 ), namely, its modest half-lives in animals, by making a chemically stable 3-alkylaminopyrazinone bioisostere for its 3-sulfonylaminopyridinone core. Compound3 (L-375,378), the closest aminopyrazinone analogue of1 , has comparable selectivity and slightly decreased efficacy but significantly improved pharmacokinetics in rats, dogs, and monkeys to1 . We have developed an efficient and versatile synthesis of3 , and this compound has been chosen for further preclinical and clinical development.- Published
- 1998
10. Nonpeptide glycoprotein IIb/IIIa inhibitors. 5. Antithrombotic effects of MK-0383.
- Author
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Lynch, J J, Cook, J J, Sitko, G R, Holahan, M A, Ramjit, D R, Mellott, M J, Stranieri, M T, Stabilito, I I, Zhang, G, and Lynch, R J
- Abstract
The antiaggregatory and antithrombotic actions of MK-0383, a low molecular weight, nonpeptide antagonist of the platelet glycoprotein IIb/IIIa, were evaluated in a variety of canine models. Inhibition of ex vivo platelet aggregation responses to ADP and collagen were observed after the acute sequential i.v. administrations of 10 to 500 micrograms/kg or 360-min continuous i.v. infusions of 1 to 10 micrograms/kg/min of MK-0383. Hemostatic function normalized within 30 (platelet response to collagen, template bleeding times) to 90 min (platelet response and sensitivity to ADP) after the termination of 360-min i.v. MK-0383 infusions, suggesting no protracted, direct effects on platelet function. With acute sequential i.v. administrations of MK-0383, platelet response to ADP was abolished without significant extension of bleeding time. In a model of platelet-dependent cyclic flow reductions in injured, stenosed left circumflex coronary artery, the bolus i.v. administrations of 300 and 1000 micrograms/kg of MK-0383 totally abolished cyclic flow reductions for periods of 18 +/- 1 and 37 +/- 5 min, respectively. In a model of electrically induced left circumflex coronary artery occlusive thrombosis, 10 micrograms/kg/min i.v. of MK-0383 initiated 15 min before electrical injury prevented occlusive thrombosis in three of six preparations despite continued electrical stimulation of the vessel for 300 min, delayed occlusion in three of six preparations (160.3 +/- 5.5 min) and reduced thrombus mass (5.1 +/- 1.3 mg), compared to the development of occlusive thrombosis in six of six saline-treated preparations (50.5 +/- 8.7 min; 19.1 +/- 3.0 mg). When administered as an adjunct to thrombolytic agents in the presence of background heparin for lysis of electrically induced left circumflex coronary artery occlusive thrombus, 10 micrograms/kg/min i.v. of MK-0383 initiated 15 min before tissue-type plasminogen activator or streptokinase increased the incidence of (tissue-type plasminogen activator: eight of nine MK-0383 vs. three of eight saline; streptokinase: eight of eight MK-0383 vs. two of eight saline) and accelerated reperfusion, and reduced the incidence of acute thrombotic reocclusion during continued MK-0383 infusion. These findings indicate significant antithrombotic potential for MK-0383 alone or as an adjunct to thrombolytic therapy in the treatment of coronary artery ischemic syndromes.
- Published
- 1995
11. Nonpeptide glycoprotein IIb/IIIa inhibitors. 8. Antiplatelet activity and oral antithrombotic efficacy of L-734,217.
- Author
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Cook, J J, Holahan, M A, Lyle, E A, Ramjit, D R, Sitko, G R, Stranieri, M T, Stupienski, R F, Wallace, A A, Hand, E L, Gehret, J R, Kothstein, T, Drag, M D, McCormick, G Y, Perkins, J J, Ihle, N C, Duggan, M E, Hartman, G D, Gould, R J, and Lynch, J J
- Abstract
The antiplatelet activity of L-734,217, a nonpeptide platelet GPIIb/IIIa antagonist, was evaluated in the rat, guinea pig and dog. IC50 for inhibition of in vitro platelet aggregation for these species (agonists: adenosine diphosphate, collagen) were rat, 838,000 and > 1,100,000 nM; guinea pig, 124 and 156 nM; dog, 42 and 50 nM. In an in vivo rat/in vitro dog platelet aggregation assay, effective antiaggregatory plasma concentrations of L-734,217 were achieved after 8.0 to 16.0 mg/kg p.o. vs. 0.3 to 1.0 mg/kg i.v. to rats. Delays in platelet-dependent hemostatic plug formation in severed mesenteric arteries were observed after 2.0 to 5.0 mg/kg p.o. vs. 0.1 to 0.2 mg/kg i.v. to guinea pigs. Dose-dependent inhibitions of ex vivo platelet aggregation after 0.3 to 3.0 mg/kg p.o. and 0.03 to 0.3 mg/kg i.v. L-734,217 to conscious dogs yielded estimates of 8 to 16% oral bioavailability. The antiplatelet activity of 3.0 mg/kg p.o. L-734,217 in dogs was unaffected by dosage form or food. In a conscious dog model of left circumflex coronary artery electrolytic lesion, 3.0 mg/kg p.o. L-734,217 q4 to 8 hr reduced thrombus mass, prevented occlusive coronary artery thrombosis and reduced or prevented myocardial infarction and ventricular ectopy. In anesthetized dogs, a dissociation between inhibition of ex vivo platelet aggregation and template bleeding time prolongation was observed with i.v. L-734,217. The results of the coadministration of heparin, aspirin and L-734,217 to anesthetized dogs suggested a synergistic effect on template bleeding time with no effect on plasma L-734,217 concentrations. These findings indicate L-734,217 to be an important lead structure for the development of therapeutically useful oral antiplatelet agents.
- Published
- 1996
12. Design and Synthesis of a Series of Potent and Orally Bioavailable Noncovalent Thrombin Inhibitors That Utilize Nonbasic Groups in the P1 Position
- Author
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Tucker, T. J., Brady, S. F., Lumma, W. C., Lewis, S. D., Gardell, S. J., Naylor-Olsen, A. M., Yan, Y., Sisko, J. T., Stauffer, K. J., Lucas, B. J., Lynch, J. J., Cook, J. J., Stranieri, M. T., Holahan, M. A., Lyle, E. A., Baskin, E. P., Chen, I-W., Dancheck, K. B., Krueger, J. A., Cooper, C. M., and Vacca, J. P.
- Abstract
As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound
1 , which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.- Published
- 1998
13. Discovery and Development of the Novel Potent Orally Active Thrombin Inhibitor N-(9-Hydroxy-9-fluorenecarboxy)prolyl trans-4-Aminocyclohexylmethyl Amide (L-372,460): Coapplication of Structure-Based Design and Rapid Multiple Analogue Synthesis on Solid Support
- Author
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Brady, S. F., Stauffer, K. J., Lumma, W. C., Smith, G. M., Ramjit, H. G., Lewis, S. D., Lucas, B. J., Gardell, S. J., Lyle, E. A., Appleby, S. D., Cook, J. J., Holahan, M. A., Stranieri, M. T., Lynch, J. J., Jr., Lin, J. H., Chen, I.-W., Vastag, K., Naylor-Olsen, A. M., and Vacca, J. P.
- Abstract
Early studies in these laboratories of peptidomimetic structures containing a basic P
1 moiety led to the highly potent and selective thrombin inhibitors2 (Ki = 5.0 nM) and3 (Ki = 0.1 nM). However, neither attains significant blood levels upon oral administration to rats and dogs. With the aim of improving pharmacokinetic properties via a more diverse database, we devised a resin-based route for the synthesis of analogues of these structures in which the P3 residue is replaced with a range of lipophilic carboxylic amides. Assembly proceeds from the common P2 −P1 template7 linked via an acid-labile carbamate to a polystyrene support. Application of the methodology in a repetitive fashion afforded several interesting analogues out of a collection of some 200 compounds. Among the most potent of the group, N-(9-hydroxy-9-fluorenecarboxy)prolyl trans-4-aminocyclohexylmethyl amide (L-372,4608 , Ki = 1.5 nM), in addition to being fully efficacious in a rat model of arterial thrombosis at an infusion rate of 10 μg/kg/min, exhibits oral bioavailability of 74% in dogs, and oral bioavailability of 39% in monkeys with a serum half-life of just under 4 h. On the basis of its favorable biological properties, inhibitor8 has been subject to further evaluation as a possible treatment for thrombogenic disorders.- Published
- 1998
14. Non-Peptide Glycoprotein IIb/IIIa Antagonists. 11. Design and in Vivo Evaluation of 3,4-Dihydro-1(1H)-isoquinolinone-Based Antagonists and Ethyl Ester Prodrugs
- Author
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Hutchinson, J. H., Cook, J. J., Brashear, K. M., Breslin, M. J., Glass, J. D., Gould, R. J., Halczenko, W., Holahan, M. A., Lynch, R. J., Sitko, G. R., Stranieri, M. T., and Hartman, G. D.
- Abstract
The structure−activity relationship of a series of orally active glycoprotein IIb/IIIa antagonists containing a nitrogen heterocycle grafted onto a 3,4-dihydro-1(1H)-isoquinolinone core is described. These compounds are structurally novel analogs of the progenitor compound
1 (L-734,217, [[3(R)-[2-(piperidin-4-yl)ethyl]-2-oxopiperidinyl]acetyl]-3(R)-methyl-β-alanine) in which the lactam chiral center has been removed. The 4-piperazinyl- and 4-piperidinyl-substituted 3,4-dihydro-1(1H)-isoquinolinones were found to be optimal for in vitro potency. In addition, substitution at the 3-position of the β-amino acid enhanced potency with the 3-pyridyl and 3-ethynyl analogs being the most potent prepared. Attempts to improve the in vivo profile of these compounds focused on modification of the physical properties. Ester prodrugs were prepared to increase the lipophilicity and remove the zwitterionic nature of the antagonists. The prodrug approach, coupled with the arylpiperazine terminus (pKa = ~9.0), afforded moderately basic and relatively nonpolar compounds. The acid N-[[7-(piperazin-1-yl)-3,4-dihydro-1(1H)-oxoisoquinolin-2-yl]acetyl]-3(S)-ethynyl-β-alanine,6d (L-767,679), is a potent fibrinogen receptor antagonist able to inhibit the ADP-induced aggregation of human gel-filtered platelets with an IC50 of 12 nM. Although6d is orally active based on the results of an ex vivo dog assay at 0.3 mg/kg, the ethyl ester prodrug of this compound,19 (L-767,685), is better absorbed at this dose than6d . Upon oral dosing, the ester19 is converted to6d in vivo in dog with an estimated oral systemic availability of >17% (0−8 h, AUC19 po /AUC6d iv ). In addition, studies in monkey at an oral dose of 1 mg/kg show that19 affects the complete inhibition of the ex vivo platelet aggregation in response to ADP between 2 and 8 h postdose with the level of inhibition remaining at 40% at 12 h postdose. This level of activity was superior to that observed for6d and1 at the same dose. Using ex vivo ADP-induced aggregation data from rhesus monkey (n = 2, 0−8 h using the AUC19 po /AUC6d iv ), the estimated systemic oral availability of6d when dosed as19 is 32%.- Published
- 1996
15. Non-Peptide Glycoprotein IIb/IIIa Inhibitors. 17. Design and Synthesis of Orally Active, Long-Acting Non-Peptide Fibrinogen Receptor Antagonists
- Author
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Askew, B. C., Bednar, R. A., Bednar, B., Claremon, D. A., Cook, J. J., McIntyre, C. J., Hunt, C. A., Gould, R. J., Lynch, R. J., Lynch, J. J., Jr., Gaul, S. L., Stranieri, M. T., Sitko, G. R., Holahan, M. A., Glass, J. D., Hamill, T., Gorham, L. M., Prueksaritanont, T., Baldwin, J. J., and Hartman, G. D.
- Abstract
The synthesis and pharmacological evaluation of
5 (L-738,167), a potent, selective non-peptide fibrinogen receptor antagonist is reported. Compound5 inhibited the aggregation of human gel-filtered platelets with an IC50 value of 8 nM and was found to be >33000-fold less effective at inhibiting the attachment of human endothelial cells to fibrinogen, fibronectin, and vitronectin than it was at inhibiting platelet aggregation. Ex vivo platelet aggregation was inhibited by >85% 24 h after the oral administration of5 to dogs at 100 μg/kg. The extended pharmacodynamic profile exhibited by5 appears to be a consequence of its high-affinity binding to GPIIb/IIIa on circulating platelets and suggests that5 is suitable for once-a-day dosing.- Published
- 1997
16. Investigation of (Oxodioxolenyl)methyl Carbamates as Nonchiral Bioreversible Prodrug Moieties for Chiral Amines
- Author
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Alexander, J., Bindra, D. S., Glass, J. D., Holahan, M. A., Renyer, M. L., Rork, G. S., Sitko, G. R., Stranieri, M. T., Stupienski, R. F., Veerapanane, H., and Cook, J. J.
- Abstract
The preparation of (oxodioxolenyl)methyl carbamates and their evaluation as novel nonchiral prodrug moieties for chiral primary and secondary amino functional drugs are described. 4-(Carbamoylmethyl)-2-oxo-1,3-dioxolene derivatives of 3,4-dimethoxyphenethylamine with 5-methyl, 5-phenyl, and 5-anisyl substitution (
5a ,5b , and5c ) on the dioxolenone ring were prepared as model amine prodrugs by a one step process involving displacement of p-nitrophenol from appropriately substituted (oxodioxolenyl)methyl p-nitrophenyl carbonates. Plasma enzyme-catalyzed dioxolenone ring opening of these carbamates led to a cascade reaction resulting in the rapid and quantitative regeneration of the parent amine drug. Aryl substitution did not significantly alter the hydrolysis rates of these dioxolenone carbamates in buffers at pH 1 and 7.4 or in rat plasma, although the hydrolysis rates of 5-phenyl- (1b ) and 5-anisyl-4-methyl-1,3-dioxol-4-en-2-one (1c ) in pH 7.4 phosphate buffer were 2−3-fold faster than that of the 5-methyl-substituted analog (1a ). Application of this prodrug strategy to the chiral fibrinogen receptor antagonist L-734,217 resulted in a prodrug that gave quantitative reconversion in rat and dog plasma in vitro and oral bioavailability of 23 ± 6% in dogs for the parent drug.- Published
- 1996
17. Antithrombotic effects of MK-0852, a platelet fibrinogen receptor antagonist, in canine models of thrombosis.
- Author
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Ramjit, D R, Lynch, J J, Sitko, G R, Mellott, M J, Holahan, M A, Stabilito, I I, Stranieri, M T, Zhang, G, Lynch, R J, and Manno, P D
- Abstract
The antiaggregatory and antithrombotic actions of MK-0852, a cyclic heptapeptide antagonist of the platelet GP IIb/IIIa, were evaluated in a variety of canine models. In vitro, MK-0852 inhibited the aggregation of canine platelet-rich plasma induced by 10 microM ADP in the presence of 1 microM epinephrine with an IC50 value of 0.10 microM. The i.v. infusion of 1.0 and 3.0 micrograms/kg/min MK-0852 to anesthetized dogs significantly inhibited ex vivo platelet aggregation responses to ADP and collagen, with the 3.0 micrograms/kg/min infusion completely inhibiting ex vivo aggregation responses to both agonists. The i.v. administrations of 100 and 300 micrograms/kg MK-0852 suppressed platelet-dependent cyclic flow reductions in stenosed canine left circumflex (LCX) coronary artery for periods of 24 +/- 3 and 64 +/- 4 min, respectively. In a canine model of copper coil-induced femoral arterial thrombosis, i.v. MK-0852 (100 micrograms/kg + 1 microgram/kg/min), initiated 15 min before coil placement, reduced the incidence of occlusive thrombosis during the 45-min post-coil time period of continued therapy (1/5 MK-0852 vs. 7/7 saline; P < .01). MK-0852 was administered as an adjunctive therapy with tPA to evaluate its effects on thrombolysis after copper coil-induced femoral arterial thrombus formation. MK-0852 (i.v.; 100 micrograms/kg + 1 microgram/kg/min), initiated 15 min before tPA, reduced the incidence of post-thrombolysis reocclusion. During the 60-min period of continued drug infusion after the termination of tPA, 0 of 5 animals receiving MK-0852 reoccluded vs. 7/8 saline (P < .01). In a canine model of electrically induced LCX coronary artery thrombosis, i.v. MK-0852 (100 micrograms/kg + 3 micrograms/kg/min), initiated 15 min before the initiation of electrical injury, prevented occlusive thrombosis in 4 of 6 preparations despite the continued electrical stimulation of the vessel for 180 min. Thrombotic occlusion was delayed in the remaining two preparations (99 and 100 min), compared with occlusion in 4 of 4 saline-treated preparations (69.3 +/- 6.3 min). When administered as an adjunct to thrombolytic agents for lysis of electrically induced LCX coronary artery thrombi, i.v. MK-0852 (300 micrograms/kg + 3 micrograms/kg/min), initiated 15 min before tPA or streptokinase, both increased the incidence of reperfusion (tPA: 8/8 MK-0852 vs. 3/8 saline; streptokinase: 5/8 MK-0852 vs. 2/8 saline) and accelerated reperfusion. The incidence of reocclusion during continued adjunctive therapy was reduced.(ABSTRACT TRUNCATED AT 400 WORDS)
- Published
- 1993
18. Nonpeptide GPllb/llla inhibitors - XVI. Thieno[2,3-b]thiophene a-sulfonamides are potent inhibitors of platelet aggregation
- Author
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Prugh, J. D., Gould, R. J., Lynch, R. J., Zhang, G., Cook, J. J., Holahan, M. A., Stranieri, M. T., Sitko, G. R., Gaul, S. L., and Bednar, R. A.
- Published
- 1997
- Full Text
- View/download PDF
19. ChemInform Abstract: Nonpeptide Glycoprotein IIb/IIIa Inhibitors. Part 13. Design and Synthesis of an Orally Active Pyrazolopiperazinone Nonpeptide Fibrinogen Receptor Antagonist.
- Author
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ASKEW, B. C., MCINTYRE, C. J., HUNT, C. A., CLAREMON, D. A., BALDWIN, J. J., ANDERSON, P. S., GOULD, R. J., LYNCH, R. J., CHANG, C. C.-T., COOK, J. J., LYNCH, J. J., HOLAHAN, M. A., SITKO, G. R., and STRANIERI, M. T.
- Published
- 1997
- Full Text
- View/download PDF
20. ChemInform Abstract: Nonpeptide GPIIB/IIIA Inhibitors. Part 10. Centrally Constrained alpha- Sulfonamides are Potent Inhibitors of Platelet Aggregation.
- Author
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EGBERTSON, M. S., HARTMAN, G. D., GOULD, R. J., BEDNAR, B., BEDNAR, R. A., COOK, J. J., GAUL, S. L., HOLAHAN, M. A., LIBBY, L. A., LYNCH, J. J. JUN., LYNCH, R. J., SITKO, G. R., STRANIERI, M. T., and VASSALLO, L. M.
- Published
- 1997
- Full Text
- View/download PDF
21. Non-peptide GPIIb/IIIa inhibitors. 20. Centrally constrained thienothiophene alpha-sulfonamides are potent, long acting in vivo inhibitors of platelet aggregation.
- Author
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Egbertson MS, Cook JJ, Bednar B, Prugh JD, Bednar RA, Gaul SL, Gould RJ, Hartman GD, Homnick CF, Holahan MA, Libby LA, Lynch JJ Jr, Lynch RJ, Sitko GR, Stranieri MT, and Vassallo LM
- Subjects
- Administration, Oral, Animals, Binding, Competitive, Bleeding Time, Blood Platelets drug effects, Blood Platelets metabolism, Dogs, Drug Evaluation, Preclinical, Female, Humans, In Vitro Techniques, Injections, Intravenous, Male, Platelet Aggregation Inhibitors chemistry, Platelet Aggregation Inhibitors pharmacology, Platelet Glycoprotein GPIIb-IIIa Complex metabolism, Radioligand Assay, Structure-Activity Relationship, Sulfonamides chemistry, Sulfonamides pharmacology, Thiophenes chemistry, Thiophenes pharmacology, Platelet Aggregation Inhibitors chemical synthesis, Platelet Glycoprotein GPIIb-IIIa Complex antagonists & inhibitors, Sulfonamides chemical synthesis, Thiophenes chemical synthesis
- Abstract
The synthesis and pharmacology of 4, a potent thienothiophene non-peptide fibrinogen receptor antagonist, are reported. Compound 4 inhibited the aggregation of human gel-filtered platelets with an IC50 of 8 nM and demonstrated an 8-fold improvement in affinity for isolated GPIIb/IIIa receptors over analogues possessing an isoindolinone backbone. Flow cytometry studies revealed that the binding of 4 to resting platelets is a diffusion-controlled process (kon = 3.3 x 10(6) M-1 s-1) and that 4 binds to dog and human platelets with comparable affinity (Kd = 0.04 and 0.07 nM, respectively). Ex vivo platelet aggregation in dogs was completely inhibited by an iv dose of 5 microg/kg [corrected], and an oral dose of 50-90 microg/kg [corrected] followed by low daily doses of 10 microg/kg [corrected] was sufficient to maintain approximately 80% inhibition of ex vivo platelet aggregation over several days. Inhibition of ADP-induced platelet aggregation in anesthetized dogs at 77 +/- 7% resulted in a moderate 2.5-fold increase in bleeding time, while complete inhibition (100%) resulted in an approximately 10-min bleeding time. Additional doses were required to increase the bleeding time to the maximum time allowed in the protocol (15 min), thus indicating a potentially useful and safe separation of efficacy and bleeding time.
- Published
- 1999
- Full Text
- View/download PDF
22. C6 modification of the pyridinone core of thrombin inhibitor L-374,087 as a means of enhancing its oral absorption.
- Author
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Isaacs RC, Cutrona KJ, Newton CL, Sanderson PE, Solinsky MG, Baskin EP, Chen IW, Cooper CM, Cook JJ, Gardell SJ, Lewis SD, Lucas RJ Jr, Lyle EA, Lynch JJ Jr, Naylor-Olsen AM, Stranieri MT, Vastag K, and Vacca JP
- Subjects
- Administration, Oral, Animals, Antithrombins administration & dosage, Biological Availability, Dogs, Pyridines chemistry, Pyridines pharmacokinetics, Pyridines pharmacology, Pyridones pharmacology, Rats, Sulfanilamides chemistry, Sulfanilamides pharmacokinetics, Sulfanilamides pharmacology, Sulfonamides pharmacology, Antithrombins chemistry, Antithrombins pharmacokinetics, Pyridones chemistry, Pyridones pharmacokinetics, Sulfonamides chemistry, Sulfonamides pharmacokinetics
- Abstract
1 (L-374,087) is a potent, selective, efficacious, and orally bioavailable thrombin inhibitor that contains a core 3-amino-2-pyridinone moiety. Replacement of the C6 pyridinone methyl group of 1 by a propyl group gave 5 (L-375,052), which retained all the excellent properties of 1, and also yielded higher plasma levels after oral dosing in dogs and rats.
- Published
- 1998
- Full Text
- View/download PDF
23. L-374,087, an efficacious, orally bioavailable, pyridinone acetamide thrombin inhibitor.
- Author
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Sanderson PE, Cutrona KJ, Dorsey BD, Dyer DL, McDonough CM, Naylor-Olsen AM, Chen IW, Chen Z, Cook JJ, Gardell SJ, Krueger JA, Lewis SD, Lin JH, Lucas BJ Jr, Lyle EA, Lynch JJ Jr, Stranieri MT, Vastag K, Shafer JA, and Vacca JP
- Subjects
- Administration, Oral, Animals, Anticoagulants administration & dosage, Anticoagulants chemistry, Biological Availability, Chlorides, Crystallography, X-Ray, Dogs, Ferric Compounds, Kinetics, Macaca fascicularis, Models, Molecular, Molecular Structure, Pyridones administration & dosage, Pyridones chemistry, Rats, Structure-Activity Relationship, Sulfonamides administration & dosage, Sulfonamides chemistry, Thrombosis drug therapy, Trypsin metabolism, Anticoagulants pharmacology, Pyridones pharmacology, Sulfonamides pharmacology, Thrombin antagonists & inhibitors
- Abstract
Replacement of the amidinopiperidine P1 group of 3-benzylsulfonylamino-6-methyl-2-pyridinone acetamide thrombin inhibitor L-373,890 (2) with a mildly basic 5-linked 2-amino-6-methylpyridine results in an equipotent compound L-374,087 (5, Ki = 0.5 nM). Compound 5 is highly selective for thrombin over trypsin, is efficacious in the rat ferric chloride model of arterial thrombosis and is orally bioavailable in dogs and cynomolgus monkeys. The structural basis for the critical importance of both methyl groups in 5 was confirmed by X-ray crystallography.
- Published
- 1998
- Full Text
- View/download PDF
24. Effects of pentobarbital on pharmacokinetics and pharmacodynamics of a potent fibrinogen receptor antagonist, L-734,217, in dogs.
- Author
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Prueksaritanont T, Stranieri MT, Hand EL, Ellis JD, Holahan MA, Sitko GR, and Cook JJ
- Subjects
- Adenosine Diphosphate antagonists & inhibitors, Adjuvants, Anesthesia administration & dosage, Animals, Area Under Curve, Collagen antagonists & inhibitors, Cross-Over Studies, Dogs, Dose-Response Relationship, Drug, Half-Life, Injections, Intravenous, Male, Pentobarbital administration & dosage, Piperidines blood, Piperidines urine, Platelet Aggregation Inhibitors blood, Platelet Aggregation Inhibitors urine, Radioimmunoassay, beta-Alanine blood, beta-Alanine pharmacokinetics, beta-Alanine urine, Adjuvants, Anesthesia pharmacology, Pentobarbital pharmacology, Piperidines pharmacokinetics, Platelet Aggregation Inhibitors pharmacokinetics, Platelet Glycoprotein GPIIb-IIIa Complex antagonists & inhibitors, beta-Alanine analogs & derivatives
- Abstract
Effects of pentobarbital on pharmacokinetics and pharmacodynamics of L-734,217, a potent fibrinogen receptor antagonist, were studied in male dogs. L-734,217 was given intravenously at 0.01 mg kg-1, in a cross-over fashion, to conscious dogs or to dogs anesthetized with pentobarbital. Plasma concentrations of L-734,217 were measured using a radioimmunoassay and inhibitory effects on ex vivo platelet aggregation induced by ADP or collagen were determined. In pentobarbital-treated dogs, L-734,217 plasma concentrations during the first 3 h collection period were significantly higher than those in the control animals. Corresponding to the increased plasma levels, the mean ex vivo inhibitory effects on ADP- or collagen-induced platelet aggregation in dogs under anesthesia appeared greater than in those without the anesthetic treatment. Pharmacokinetic analysis revealed a modest, but significant (up to 40%) elevation in the area under the plasma concentration-time curve during 6 h of the drug administration, and a reduction in L-734,217 plasma clearance and volumes of distribution, in the anesthetized dogs. Analysis of pharmacodynamic data indicated that the EC50 and the Hill coefficient of the platelet aggregation response-plasma concentration curve were not altered by pentobarbital treatment. The results are in agreement with the findings that the administration of pentobarbital alone (in the absence of L-734,217) did not affect appreciably the ex vivo platelet aggregatory responses. In a separate group of dogs, L-734,217 was found to be metabolically stable, and was eliminated unchanged renally (64 +/- 4%) and hepatically (32 +/- 6%). In addition, L-734,217 did not bind substantially to canine plasma proteins or blood cellular components. It is possible that alterations of regional hemodynamics, reportedly mediated by pentobarbital, contributed to changes observed in the present study. That is, alterations occurred in L-734,217 elimination and distribution processes which resulted in an increase in drug plasma levels. Since pentobarbital anesthesia influenced only the pharmacokinetics, and not the pharmacodynamics, of L-734,217, the apparent increases in the inhibition of platelet aggregation responses observed following L-734,217 administration to the anesthetized dogs were probably sequential effects of the pharmacokinetic interactions.
- Published
- 1997
- Full Text
- View/download PDF
25. Nonpeptide glycoprotein IIb/IIIa inhibitors. 15. Antithrombotic efficacy of L-738,167, a long-acting GPIIb/IIIa antagonist, correlates with inhibition of adenosine diphosphate-induced platelet aggregation but not with bleeding time prolongation.
- Author
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Cook JJ, Sitko GR, Holahan MA, Stranieri MT, Glass JD, Askew BC, McIntyre CJ, Claremon DA, Baldwin JJ, Hartman GD, Gould RJ, and Lynch JJ Jr
- Subjects
- Adenosine Diphosphate pharmacology, Animals, Azepines administration & dosage, Azepines therapeutic use, Disease Models, Animal, Dogs, Drug Administration Routes, Fibrinolytic Agents administration & dosage, Fibrinolytic Agents therapeutic use, Macaca mulatta, Pan troglodytes, Platelet Aggregation Inhibitors administration & dosage, Platelet Aggregation Inhibitors therapeutic use, Sulfonamides administration & dosage, Sulfonamides therapeutic use, Thrombosis prevention & control, Adenosine Diphosphate antagonists & inhibitors, Azepines pharmacology, Bleeding Time, Fibrinolytic Agents pharmacology, Platelet Aggregation drug effects, Platelet Aggregation Inhibitors pharmacology, Platelet Glycoprotein GPIIb-IIIa Complex antagonists & inhibitors, Sulfonamides pharmacology
- Abstract
The nonpeptide platelet glycoprotein IIb/IIIa antagonist, L-738, 167, was characterized in dog and nonhuman primate. In an anesthetized canine model of coronary artery electrolytic lesion, L-738,167 elicited dose-dependent (3, 4, 4.5 and 5 micrograms/kg i.v.) decreases in incidence of occlusion, reductions in thrombus mass and elevations in bleeding time. Antithrombotic efficacy correlated with inhibition of adenosine diphosphate-induced platelet aggregation but was dissociated from marked bleeding time elevation. Similarly, suppression of platelet-dependent cyclic flow reductions with L-738,167 in the canine coronary artery (5 micrograms/kg i.v.) and African green monkey carotid artery (10 micrograms/kg i.v.) correlated with inhibition of adenosine diphosphate-induced platelet aggregation but not with inhibition of thrombin-induced platelet aggregation or significant prolongation of bleeding time. In conscious dogs and sedated chimpanzees, single dose intravenous bolus (5-20 micrograms/kg) and oral (25-200 micrograms/kg) administration of L-738,167 exhibited long duration (> or = 8 hr) inhibition of ex vivo platelet aggregation. Once daily oral administration to conscious dogs (10-30 micrograms/kg/day for 15 days) and rhesus monkeys (200-250 micrograms/kg/day for 11 days) maintained significant but submaximal (50-90% inhibition) trough levels of inhibition of adenosine diphosphate-induced ex vivo platelet aggregation. Platelet sensitivity to adenosine diphosphate after multiple days of oral dosing in dogs was similar to pretreatment sensitivity. L-738,167 showed characteristics suitable for chronic oral therapy with a glycoprotein IIb/IIIa inhibitor.
- Published
- 1997
26. Non-peptide glycoprotein IIb/IIIa antagonists. 11. Design and in vivo evaluation of 3,4-dihydro-1 (1H)-isoquinolinone-based antagonists and ethyl ester prodrugs.
- Author
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Hutchinson JH, Cook JJ, Brashear KM, Breslin MJ, Glass JD, Gould RJ, Halczenko W, Holahan MA, Lynch RJ, Sitko GR, Stranieri MT, and Hartman GD
- Subjects
- Animals, Dogs, Drug Design, Evaluation Studies as Topic, Female, Humans, Isoquinolines chemistry, Isoquinolines pharmacology, Macaca mulatta, Magnetic Resonance Spectroscopy, Male, Platelet Aggregation Inhibitors chemistry, Platelet Aggregation Inhibitors pharmacology, Structure-Activity Relationship, Isoquinolines chemical synthesis, Platelet Aggregation Inhibitors chemical synthesis, Platelet Glycoprotein GPIIb-IIIa Complex antagonists & inhibitors
- Abstract
The structure-activity relationship of a series of orally active glycoprotein IIb/IIIa antagonists containing a nitrogen heterocycle grafted onto a 3,4-dihydro-1 (1H)-isoquinolinone core is described. These compounds are structurally novel analogs of the progenitor compound 1 (L-734,217,[[3(R)-[2-(piperidin-4-yl)ethyl]-2-oxopiperidinyl ]acetyl]-3(R)- methyl-beta-alanine) in which the lactam chiral center has been removed. The 4-piperazinyl- and 4-piperidinyl-substituted 3,4-dihydro-1(1H)-isoquinolinones were found to be optimal for in vitro potency. In addition, substitution at the 3-position of the beta-amino acid enhanced potency with the 3-pyridyl and 3-ethynyl analogs being the most potent prepared. Attempts to improve the in vivo profile of these compounds focused on modification of the physical properties. Ester prodrugs were prepared to increase the lipophilicity and remove the zwitterionic nature of the antagonists. The prodrug approach, coupled with the arylpiperazine terminus (pKa = approximately 9.0), afforded moderately basic and relatively nonpolar compounds. The acid N-[[7-(piperazin-1-yl)-3,4-dihydro-1(1H)-oxoisoquinolin-2-yl ]acetyl]-3(S)- ethynyl-beta-alanine, 6d (L-767,679), is a potent fibrinogen receptor antagonist able to inhibit the ADP-induced aggregation of human gel-filtered platelets with an IC50 of 12 nM. Although 6d is orally active based on the results of an ex vivo dog assay at 0.3 mg/kg, the ethyl ester prodrug of this compound, 19 (L-767,685), is better absorbed at this dose than 6d. Upon oral dosing, the ester 19 is converted to 6d in vivo in dog with an estimated oral systemic availability of > 17% (0-8 h, AUC19po/AUC6div). In addition, studies in monkey at an oral dose of 1 mg/kg show that 19 affects the complete inhibition of the ex vivo platelet aggregation in response to ADP between 2 and 8 h postdose with the level of inhibition remaining at 40% at 12 h postdose. This level of activity was superior to that observed for 6d and 1 at the same dose. Using ex vivo ADP-induced aggregation data from rhesus monkey (n = 2, 0-8 h using the AUC19po/AUC6div), the estimated systemic oral availability of 6d when dosed as 19 is 32%.
- Published
- 1996
- Full Text
- View/download PDF
27. Species variability in platelet and other cellular responsiveness to thrombin receptor-derived peptides.
- Author
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Connolly TM, Condra C, Feng DM, Cook JJ, Stranieri MT, Reilly CF, Nutt RF, and Gould RJ
- Subjects
- Amino Acid Sequence, Animals, Blood Platelets ultrastructure, Cell Line, Cricetinae, DNA Replication drug effects, Dogs blood, Fibroblasts drug effects, Guinea Pigs, Humans, Male, Molecular Sequence Data, Muscle, Smooth, Vascular drug effects, Peptide Fragments chemical synthesis, Primates blood, Rats, Receptors, Thrombin chemistry, Rodentia blood, Species Specificity, Swine blood, Mammals blood, Peptide Fragments pharmacology, Platelet Aggregation drug effects, Receptors, Thrombin physiology
- Abstract
The aggregation of platelets from a variety of animal species in response to thrombin receptor-derived activating peptides was evaluated. A series of 14-(SFLLRNPNDKYEPF), 7-(SFLLRNP-NH2), 6-(SFLLRN-HN2) or 5-(SFLLR-NH2) residue peptides, the structures of which were based on the deduced amino acid sequence of the human thrombin receptor, promoted full aggregation of platelets in plasma from humans, African Green and Rhesus monkeys, baboons and guinea pigs at 4-50 microM depending on the peptide used. Platelets in plasma from rabbit, dog, pig, and hamster underwent a shape change but failed to aggregate in response to these peptides over 3 log units of peptide up to 800 microM, despite being fully responsive to human thrombin. However, because the receptor peptides induced shape change in the platelets from these non-aggregating species, they apparently can activate some of the intracellular signaling system(s) usually initiated by thrombin in these platelets. In contrast, platelets from rats did not undergo shape change or aggregate in response to the peptides. A 7-residue receptor-derived peptide based on the deduced amino acid sequence of the clone of the hamster thrombin receptor (SFFLRNP-N2) was nearly as efficacious as the corresponding human receptor-derived 7-residue peptide to promote aggregation of human platelets. However, the hamster peptide could not promote aggregation of hamster platelets in plasma at up to 800 microM peptide, while a shape change response was elicited. Platelets from rats, rabbits and pigs also did not aggregate in response to this peptide derived from the hamster thrombin receptor, but all species except the rat underwent a shape change.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1994
28. Pharmacokinetics and pharmacodynamics of L-703,014, a potent fibrinogen receptor antagonist, after intravenous and oral administration in the dog.
- Author
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Barrett JS, Gould RJ, Ellis JD, Holahan MM, Stranieri MT, Lynch JJ Jr, Hartman GD, Ihle N, Duggan M, and Moreno OA
- Subjects
- Administration, Oral, Animals, Biological Availability, Chromatography, Gel, Dipeptides administration & dosage, Dipeptides blood, Dogs, Erythrocytes metabolism, Feces chemistry, Indoles administration & dosage, Indoles blood, Injections, Intravenous, Spectrometry, Fluorescence, Dipeptides pharmacokinetics, Indoles pharmacokinetics, Platelet Membrane Glycoproteins antagonists & inhibitors
- Abstract
The pharmacokinetics and pharmacodynamics of L-703,014, a fibrinogen receptor antagonist, have been examined in the dog. An analytical method which utilizes methanol precipitation of dog plasma proteins followed by HPLC with an automated column switching technique using the chemical analogue L-704,326 as internal standard was developed for the determination of L-703,014 in dog plasma. The compound was not metabolized in the dog and was eliminated in the kidneys and into bile. Of the administered dose, 68.9 +/- 1.3% (i.v.) and 80.5 +/- 11.9% (p.o.) were recovered in the feces; 20.3 +/- 1.3% (i.v.) and 2.2 +/- 0.2% (p.o.) were recovered in the urine by 72 hr. L-703,014 was 23 +/- 3.4% bound in dog plasma protein and the mean ratio of plasma/whole blood was 1.22 +/- 0.05. The mean terminal half-life was 118 +/- 36 min, the mean steady-state volume of distribution was 0.61 +/- 0.22 L/kg, and the mean plasma clearance was 8 +/- 2 mL/min/kg. Ex vivo platelet aggregation measurements were made by inducing platelet aggregation with 10 micrograms/mL collagen in the presence of 1 microM epinephrine as an agonist. The mean C50 was 44.4 +/- 6.0 ng/mL, and the mean Hill coefficient was 1.5 +/- 0.3. The mean bioavailability was 4.9 +/- 1.4% in dogs administered 2.0 mg/kg (p.o.).
- Published
- 1994
- Full Text
- View/download PDF
29. Effect of E-4031, a class III antiarrhythmic agent, on experimental infarct size in a canine model of myocardial ischemia-reperfusion injury.
- Author
-
Holahan MA, Stranieri MT, Stabilito II, and Lynch JJ Jr
- Subjects
- Animals, Coronary Circulation physiology, Dogs, Female, Hemodynamics drug effects, Male, Myocardial Infarction pathology, Myocardial Infarction physiopathology, Myocardial Reperfusion Injury physiopathology, Ventricular Fibrillation physiopathology, Anti-Arrhythmia Agents therapeutic use, Myocardial Infarction drug therapy, Myocardial Reperfusion Injury drug therapy, Piperidines therapeutic use, Pyridines therapeutic use
- Abstract
Class III antiarrhythmic agents such as E-4031 have demonstrated efficacy in preventing and/or terminating malignant ventricular arrhythmias in experimental models. It has recently been suggested that Class III agents might possess additional antiischemic properties that may translate into a reduction in the frequency or severity of arrhythmia. The potential for the Class III antiarrhythmic agent E-4031 to limit the extent of developing myocardial infarction was assessed in a barbiturate-anesthetized canine model of ischemic-reperfusion injury. Untreated control (n = 13) and E-4031-treated animals (n = 8, 300 micrograms/kg, i.v., immediately preceding myocardial ischemia) were subjected to a 90-min period of left circumflex coronary artery occlusion followed by a 5-h period of reperfusion. The predominant hemodynamic effect displayed by E-4031 was a reduction in heart rate throughout the period of coronary artery occlusion and early reperfusion. Areas at risk of infarction, expressed as percentages of left ventricle, were equivalent in the control and E-4031 treatment groups (38.5 +/- 1.0 and 34.6 +/- 1.9%, respectively). Posterolateral myocardial infarct sizes, expressed either as percentages of risk area or of total left ventricle, were reduced slightly but not significantly in the E-4031 treatment group compared to the control group (35.2 +/- 5.6 and 45.4 +/- 3.0% of risk area, respectively; 12.7 +/- 2.4 and 17.6 +/- 1.4% of left ventricle, respectively). Regional myocardial blood flows in nonischemic and central ischemic zones of myocardium did not differ significantly between the control and E-4031 treatment groups before and during the period of coronary artery occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1992
- Full Text
- View/download PDF
30. Effects of the novel coronary selective calcium channel blocker, McN-6186, on cardiocirculatory dynamics, coronary vascular resistance, and cardiac output distribution in normal, conscious rats.
- Author
-
Flaim SF, Stranieri MT, Gill A, Carson JR, and Brannan MD
- Subjects
- DOM 2,5-Dimethoxy-4-Methylamphetamine analogs & derivatives, Animals, Blood Gas Analysis, Cerebrovascular Circulation drug effects, Hemodynamics drug effects, Hydrogen-Ion Concentration, Male, Microspheres, Muscles blood supply, Nifedipine pharmacology, Rats, Rats, Inbred Strains, Regional Blood Flow drug effects, Vascular Resistance drug effects, DOM 2,5-Dimethoxy-4-Methylamphetamine pharmacology, Amphetamines pharmacology, Calcium Channel Blockers pharmacology, Cardiac Output drug effects, Coronary Circulation drug effects
- Abstract
The purpose of this study was to characterize the cardiocirculatory effects of the novel calcium channel blocker, McN-6186 (McN), normal, conscious rats. Animals were instrumented under halothane anesthesia for right atrial, left ventricular, arterial, and venous pressure recordings. The radioactive microsphere technique was used to measure regional blood flow (RBF) and cardiac output (CO) before (control) and during intravenous (i.v.) infusion of either McN at three doses (0.03, 0.1, 0.3 mg/kg) or vehicle at an equal infusion rate (0.0408 ml/min). Nifedipine (NIF) was also studied at three similar blood pressure (BP)-lowering doses (0.025, 0.150, and 0.375 mg/kg). The predominant effect of McN in conscious rats was to cause coronary vasodilation. The coronary vasodilator potency of McN was similar to NIF (ED25, McN = 0.03 mg/kg, NIF = 0.025 mg/kg). Neither McN nor NIF significantly changed systemic vascular resistance (SVR) over their respective coronary vasodilator dose ranges, suggesting that both compounds are selective coronary vasodilators. The doses of McN and NIF that reduced mean arterial pressure (MAP) by 25% (ED25) were similar (McN = 0.3 mg/kg, NIF = 0.375 mg/kg). At equal BP-lowering doses, McN increased coronary flow by 145% versus 110% for NIF. McN did not have major effects on other regions of the peripheral circulation. There was, however, some vasodilator activity in the renal and cerebral vascular beds. Because McN reduced coronary vascular resistance at a dose lower than that required to reduce resistance in other vascular beds, this compound appears to be a selective coronary vasodilator and may have therapeutic efficacy as an antianginal agent.
- Published
- 1990
- Full Text
- View/download PDF
31. Effects of the novel calcium channel blocker, McN-5691, on cardiocirculatory dynamics and cardiac output distribution in conscious spontaneously hypertensive rat.
- Author
-
Flaim SF, Stranieri MT, Gill A, Carson JR, and Brannan MD
- Subjects
- Animals, Calcium Channel Blockers administration & dosage, Coronary Circulation drug effects, Infusions, Intravenous, Male, Propylamines administration & dosage, Rats, Rats, Inbred SHR, Rats, Inbred WKY, Vascular Resistance drug effects, Calcium Channel Blockers pharmacology, Cardiac Output drug effects, Hemodynamics drug effects, Hypertension drug therapy, Propylamines pharmacology
- Abstract
The purpose of this study was to characterize the cardiocirculatory effects of McN-5691 in the conscious spontaneously hypertensive rat (SHR) and in age matched Wistar-Kyoto (WKY) control rats. Animals were instrumented under halothane anesthesia for right atrial, left ventricular arterial, and venous pressure recordings. The radioactive microsphere technique was used to estimate regional blood flow and cardiac output before (control) and during intravenous (i.v.) infusion of either McN-5691 at three dosage levels (0.3, 1.0, 3.0 mg/kg), or vehicle (VH) at an infusion rate of 0.0408 ml/min. The predominant hemodynamic effect of McN-5691 (cumulative dose = 0.3-4.3 mg/kg i.v.) in conscious SHR was dose-related reduction in mean arterial pressure with normalization occurring at a cumulative dose of 1.3 mg/kg i.v. The antihypertensive effect of McN-5691 was accompanied by reductions in left ventricular peak systolic pressure (cumulative dose = 1.0-4.3 mg/kg i.v.), arterial pressure-rate product (1.3-4.3 mg/kg i.v.), and systemic vascular resistance (4.3 mg/kg i.v.). McN-5691 had no statistically significant effect on heart rate or cardiac contractility as measured by dP/dt/peak left ventricular pressure. The predominant peripheral vascular effects of McN-5691 were increases in skeletal muscle blood flow (4.3 mg/kg i.v.) and reductions in skeletal muscle (1.3-4.3 mg/kg i.v.), renal (1.3-4.3 mg/kg i.v.), gastrointestinal (4.3 mg/kg i.v.), and coronary (1.3-4.3 mg/kg i.v.) vascular resistances. Despite the fall in renal vascular resistance, renal blood flow was not changed by McN-5691. McN-5691 did not have major effects on other regions of the peripheral circulation. Thus, McN-5691 is an antihypertensive agent as defined by its ability to normalize blood pressure in the SHR, and the hemodynamic mechanism leading to this effect is reduction in peripheral vascular resistance. This antihypertensive effect is not accompanied by reflex tachycardia and is not associated with negative inotropic activity or detrimental peripheral circulatory changes in the conscious SHR.
- Published
- 1988
- Full Text
- View/download PDF
32. Effects of bepridil hydrochloride on cardiocirculatory dynamics, coronary vascular resistance, and cardiac output distribution in normal, conscious rats.
- Author
-
Flaim SF, Stranieri MT, and Mathiasen JR
- Subjects
- Animals, Bepridil, Blood Gas Analysis, Cerebrovascular Circulation drug effects, Hydrogen-Ion Concentration, Male, Muscles blood supply, Rats, Rats, Inbred Strains, Regional Blood Flow drug effects, Renal Circulation drug effects, Anti-Arrhythmia Agents pharmacology, Cardiac Output drug effects, Coronary Circulation drug effects, Pyrrolidines pharmacology, Vascular Resistance drug effects
- Abstract
The purpose of this study was to characterize the cardiocirculatory effects of bepridil hydrochloride (BP) in the normal, conscious rat. Animals were instrumented under halothane anesthesia for right atrial, left ventricular, arterial, and venous pressure recordings. The radioactive-microsphere technique was used to measure regional blood flow and cardiac output before (control) and during intravenous (i.v.) infusion of either BP at three dosage levels (3.0, 6.0, 12.0 mg/kg) or vehicle (VH) at infusion rates matching those of the BP protocol (0.0408 ml/min). The predominant effects of BP (cumulative dose = 9.0 mg/kg i.v.) in the conscious rat were reduced coronary vascular resistance and heart rate. BP showed selectivity for the coronary circulation since systemic vascular resistance was not significantly reduced until a cumulative i.v. dosage of 21.0 mg/kg was administered. BP had few effects on other regions of the peripheral circulation. BP (21 mg/kg) reduced blood flow and increased vascular resistance in the arterial circulations of four of six skeletal muscles studied although opposite effects occurred in two of six muscles studied. BP had no significant effect on blood flow or vascular resistance in the other major arterial circulations. The results of this study show that BP is a selective coronary vasodilator that also reduces the primary indices of myocardial oxygen demand. These results suggest that the clinical therapeutic antianginal efficacy of BP occurs through a combined effect to increase myocardial oxygen supply and to reduce myocardial oxygen demand.
- Published
- 1988
- Full Text
- View/download PDF
33. Effects of mefenidil hydrochloride on cerebral blood flow in conscious and anesthetized rat.
- Author
-
Flaim SF, Stranieri MT, Mathiasen JR, and Brannan MD
- Subjects
- Animals, Blood Circulation drug effects, Cardiac Output drug effects, Cerebrovascular Circulation drug effects, Collateral Circulation drug effects, Coronary Vessels drug effects, Evaluation Studies as Topic, Hemodynamics drug effects, Hydrogen-Ion Concentration, Imidazoles administration & dosage, Injections, Intravenous, Male, Oxygen blood, Rats, Rats, Inbred Strains, Vascular Resistance drug effects, Imidazoles pharmacology
- Abstract
The purpose of this study was to determine the effects of the putative cerebral vasodilator, mefenidil hydrochloride (MF), on cardiocirculatory dynamics and the total distribution of cardiac output in the conscious rat. The radioactive microsphere technique was used to measure regional blood flow and cardiac output before (control) and during intravenous infusion of either MF (2.5, 5.0, 10.0 mg/kg) or vehicle (VH; saline, 0.0204, 0.0408. 0.0816 ml/min, respectively). Neither MF nor VH were found to have significant effects on cerebral blood flow or vascular resistance in conscious rats. MF significantly increased cerebral blood flow and lowered cerebral vascular resistance compared to VH in anesthetized animals without having significant effects in other circulatory regions.
- Published
- 1986
- Full Text
- View/download PDF
34. Antiarrhythmic and antifibrillatory properties of McN-4130 in several animal models.
- Author
-
Damiano BP, Sit SP, Fortunato MA, Stranieri MT, and Brannan MD
- Subjects
- Anesthesia, Animals, Blood Pressure drug effects, Coronary Disease physiopathology, Coronary Vessels physiology, Disease Models, Animal, Dogs, Electrophysiology, Female, Heart Rate drug effects, Male, Swine, Ventricular Fibrillation physiopathology, Anti-Arrhythmia Agents, Indoles pharmacology
- Abstract
McN-4130 is an experimental compound having antiarrhythmic and antifibrillatory activity in several animal models. In anesthetized, open-chest pigs subjected to total occlusion and subsequent reperfusion of the left anterior descending coronary artery, McN-4130 dose-dependently (2.5-10.0 mg/kg i.v.) protected against fibrillation and death. Mean arterial pressure was not significantly affected, but heart rate was dose-dependently reduced. In anesthetized normal dogs, McN-4130 increased ventricular fibrillation threshold for up to 45 min. This increase in fibrillation threshold was associated with concurrent increases in ventricular conduction time and ventricular effective refractory period. In conscious dogs subjected to occlusion of the left anterior descending coronary artery 24 h previously, McN-4130, 2.5 and 5.0 mg/kg i.v., significantly reduced the rate of ventricular arrhythmias for up to 45 min. McN-4130 was more effective and had a longer duration of action than comparable doses of lidocaine and disopyramide. McN-4130 was orally effective in this model at 10 mg/kg. These results indicate that McN-4130, a structurally unique experimental antiarrhythmic compound, may be useful as a ventricular antiarrhythmic agent with antifibrillatory properties.
- Published
- 1988
- Full Text
- View/download PDF
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