Chapter 11. Future Antithrombotic Therapy

Jakubowski, Joseph A.; Smith, Gary; Sall, Daniel J.

doi:10.1016/s0065-7743(08)60409-1

Cited by 32 publications

(5 citation statements)

References 57 publications

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“…[14][15][16] It is expected that the higher intrinsic potency of GP IIb-IIIa antagonists compared to aspirin will translate into better clinical efficacy in preventing arterial thrombus formation. 14,17 Indeed, this has been demonstrated with the chimeric Fab fragment of the anti-GP IIb-IIIa monoclonal antibody 7E3 (c7E3) in high-risk angioplasty patients in a phase III clinical trial. 18,19 In the meantime, a large number of potent and selective GP IIb-IIIa antagonists, including snake venom polypeptides and linear and cyclic peptides, as well as non-peptide inhibitors have been identified.…”

Section: Introductionmentioning

confidence: 98%

“…In this way, the platelets are cross-linked and thrombus growth is initiated . Due to the release and formation of a variety of platelet activators (e.g., ADP, thrombin, collagen, serotonin, thromboxane A 2 , epinephrine), additional platelets are activated and recruited to the growing thrombus. − The efficacy of existing antiplatelet agents, such as aspirin which inhibits only one agonist pathway, is limited. − It is expected that the higher intrinsic potency of GP IIb-IIIa antagonists compared to aspirin will translate into better clinical efficacy in preventing arterial thrombus formation. , Indeed, this has been demonstrated with the chimeric Fab fragment of the anti-GP IIb-IIIa monoclonal antibody 7E3 (c7E3) in high-risk angioplasty patients in a phase III clinical trial. , …”

Section: Introductionmentioning

confidence: 99%

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Orally Active Fibrinogen Receptor Antagonists. 2. Amidoximes as Prodrugs of Amidines

et al. 1996

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The potent and selective GP IIb-IIIa antagonist lamifiban (1, Ro 44-9883) is currently in clinical development as an injectable antithrombotic agent for treating and preventing acute coronary syndromes. However, for secondary prevention of thrombotic occlusions, orally active inhibitors are needed. By means of a prodrug strategy, the modest oral absorption of 1 in mice was improved by a factor of 9. In addition, these studies demonstrated that an amidoxime group can serve as a prodrug functionality for an amidino group. Application of this principle to the structurally related amidino carboxylate 13 led to the amidoxime ester 18 which was absorbed approximately 20 times better, after oral administration to mice, than 13. Due to the modification of the amidino group as well as of the carboxylate group, 18 completely lost its ability to interact with purified platelet GP IIb-IIIa. After oral administration of 18 to rats, dogs, and rhesus monkeys, the bioavailability of the active derivative 13 was 26 +/- 5, 25 +/- 6, and 33 +/- 6%, respectively, and the elimination half-life was 4.1 +/- 1.7, 11.4 +/- 1.1, and 5.1 +/- 1.4 h, respectively. On the basis of these properties, the orally active 18 (Ro 48-3657), a double prodrug of the potent and selective non-peptide GP IIb-IIIa antagonist 13 (Ro 44-3888), was selected as clinical candidate for evaluation as a prophylactic agent in patients at high risk for arterial thrombosis.

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Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Orally Active Fibrinogen Receptor Antagonists. 2. Amidoximes as Prodrugs of Amidines

et al. 1996

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“…It is known that adenosine, by means of interaction with A 2A receptors, inhibits platelet aggregation providing potential therapeutic utility in the treatment and prevention of a variety of cardiovascular and cerebrovascular diseases, including unstable angina, acute myocardial infarction, stroke, and transient ischemic attacks [Jakubowski et al, 1992]. To characterize A 2A receptors in human platelets, we performed radioligand binding and functional studies.…”

Section: A 2a Adenosine Receptors In Human Plateletsmentioning

confidence: 99%

Adenosine A2A receptors of human circulating blood elements

et al. 1998

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Recent studies have clearly shown that the adenosine A2A receptors are present in a variety of peripheral tissues, including smooth muscle cells, heart muscle and coronary arteries, and human circulating blood elements. This paper reviews the studies performed by our research group on the A2A receptors on human platelets, lymphocytes, and neutrophils. Affinity and potency of typical adenosine receptor ligands were compared in binding and functional studies as adenylyl cyclase, aggregation, and superoxide anion production assays. Saturation experiments, performed by using the selective A2A adenosine receptor antagonist [3H]SCH 58261 (5‐amino‐7‐(2‐phenylethyl)‐2‐(2‐furyl)‐pyrazolo‐[4,3‐e]‐1,2,4‐triazolo‐[1,5c] pyrimidine) revealed a single class of binding sites in all different preparations examined with affinity values in the nanomolar range (0.85–1.34 nM) and Bmax values ranging from 35 to 80 fmol/mg protein. Competition experiments showed that the potency order of agonists and antagonists studied was similar in all human circulating blood elements. In the functional assays, the same compounds exhibited a rank order of potency identical to that observed in binding experiments. Moreover, an excellent rank order correlation was found between cAMP accumulation, aggregation, and superoxide anion production data by adenosine receptor agonists and antagonists examined. Thermodynamic data indicated that [3H]SCH 58261 binding to human lymphocytes and neutrophils is entropy and enthalpy driven, a finding in agreement with the thermodynamic behaviour of antagonists binding to rat striatal A2A adenosine receptors. Drug Dev. Res. 45:253–260, 1998. © 1998 Wiley‐Liss, Inc.

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“…The TXA, receptor (TP), the protein responsible for the platelet aggregation activity of TXA,, is also able to bind PGH, [46,47]. The aminoacid sequence of TP has been recently identified [161 to belong to the G protein-coupled receptor (GPCR) family having the characteristic seven transmembrane segments.…”

Section: New Iwtential Dual Blockers Of Tfikoiciboxane Synthase and Tmentioning

confidence: 99%

Design of new potential 5-lipoxygenase inhibitors, dual thromboxane synthase inhibitors, and thromboxane a2 receptor antagonists byAM1

Albuquerque

Rodrigues

Alencastro

et al. 1995

Int. J. Quantum Chem.

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HLeukotrienes and thromboxane A , are autacoids derived from arachidonic acid (5,8,11,14-icosatretraenoic acid). They are synthesized in cells by 5-lipoxygenase and thromboxane synthase, respectively. Leukotrienes are related to inflammatory and allergic diseases, while thromboxane A is a potent platelet aggregating and vasoconstrictor agent involved in cardiovascular pathologies. In this article we have calculated partial potential energy surfaces at the AM^ level for some 5-lipoxygenase inhibitors, thromboxane synthase inhibitors, thromboxane A , receptor antagonists, and a dual blocker which inhibits thromboxane synthase and antagonizes thromboxane A, receptor. Our objective was to identify stereoelectronic properties and topographical requirements for these compounds that could be related to their biological activities. Based on our results and on molecular mechanisms of pharmacological action, we were able to propose new potential 5-lipoxygenase inhibitors and dual blockers derived from pyrazole, pyrrole, 1,2,3-triazole, and 1,2,4-triazole.

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Chapter 11. Future Antithrombotic Therapy

Cited by 32 publications

References 57 publications

Orally Active Fibrinogen Receptor Antagonists. 2. Amidoximes as Prodrugs of Amidines

Orally Active Fibrinogen Receptor Antagonists. 2. Amidoximes as Prodrugs of Amidines

Adenosine A2A receptors of human circulating blood elements

Design of new potential 5-lipoxygenase inhibitors, dual thromboxane synthase inhibitors, and thromboxane a2 receptor antagonists byAM1

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