Preparation and biological activity of novel tricyclic GPIIb/IIIa antagonists

Robarge, Kirk; Dina, Michael S.; Somers, T. C.; Lee, Arthur; Rawson, Thomas E.; Olivero, Alan G.; Tischler, Maureen H.; Webb, Robert R.; Weese, Kenneth J.; Aliagas, Ignacio; Blackburn, Brent

doi:10.1016/s0968-0896(98)80013-8

Cited by 14 publications

(5 citation statements)

References 35 publications

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“…Benzodiazepinediones are antithrombotics, antitumor and ethanol intoxication antagonists, and antibiotic agents with potential application as enzyme inhibitors and herbicides. − The synthetic pathways to these compounds are varied and have involved polymer-supported amino acids cyclization with 2-nitrobenzoic acids or protected anthranilic acids, cyclization of certain dipeptides derived from Boc anthranilic acid and α-amino acid methyl esters or by reaction of N -carboxy-α-amino acid anhydrides with Boc anthranilic acid, and liquid-phase combinatorial synthesis . Another route is directly converted isatoic anhydride to 1,4-benzodiazepine-2,5-diones through cyclocondensation with amino acids at room temperature or by fusion of their uncyclized intermediates at high temperature .…”

Section: Seven-membered Heterocycles With Two Heteroatomsmentioning

confidence: 99%

Solvent-Free Heterocyclic Synthesis

et al. 2009

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Clarissa P. Frizzo was born in Ivora ´, Rio Grande do Sul state, Brazil, in 1983. She received her undergraduate degree in Pharmacy from the Federal University of Santa Maria in 2005, and in 2007 she obtained her M.Sc. degree from the Federal University of Santa Maria, under the supervision of Professor Marcos A. P. Martins, working with the use of ionic liquids in the synthesis of heterocycles. She started her Ph.D. studies under the supervision of Professor Marcos A. P. Martins, and currently she is focusing on her Sandwich Ph.D. in the Universidade Nacional de Educacio ´n a Distancia in Spain, under the guidance of Professor Rosa M. Claramunt Vallespı ´, where she is studying the supramolecular structure of heterocycles. Dayse das Neves Moreira was born in Canguc ¸u, Rio Grande do Sul state, Brazil, in 1984. She received her undergraduate degree in Chemistry from the Federal University of Pelotas, RS, in 2006, and in 2008 she received her M.S. degree, from the Federal University of Santa Maria, RS, Brazil, working under the direction of Professor Marcos A. P. Martins, working with the use of ionic liquids in the synthesis of heterocycles. Currently, she is a Ph.D. student with Professor Marcos A. P. Martins in the Department of Chemistry of the Federal University of Santa Maria. Her major research interest is to develop new methodologies to synthesize heterocyclic compounds. Lilian Buriol was born in Santa Izabel do Oeste, Parana ´(PR) state, Brazil, in 1984. She received her undergraduate degree in Chemistry from the State University of Centro-Oeste (PR). In 2008, she completed her M.S. degree at the same university under the supervision of Professor Yohandra R. Torres, working with oil and ethanol extracts of propolis. After that, she started her Ph.D. studies in the Department of Chemistry of the Federal University of Santa Maria under the supervision of Professor Marcos A. P. Martins. Her research interest is to develop new methodologies to synthesize heterocyclic compounds along the lines of green chemistry.

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Section: Seven-membered Heterocycles With Two Heteroatomsmentioning

confidence: 99%

Solvent-Free Heterocyclic Synthesis

et al. 2009

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“…104 An alternate framework utilized a tricyclic nucleus such as in G7453, which is slightly more potent than inhibitors containing the bicyclic nucleus (IC 50 ) 54 nM, ADPinduced platelet aggregation). 105 The benzodiazepine scaffold was also independently investigated by SmithKline Beecham scientists who began their search for nonpeptide antagonists through examination of the NMR and X-ray crystal structure of their potent cyclic peptide, SK&F 107260. 106 Major and minor conformers of SK&F 107260 were determined in solution, the minor conformer being the same conformer seen in the crystal structure.…”

Section: Design Of Nonpeptide Antagonists For Oral Administrationmentioning

confidence: 99%

“…The carbamate ethyl ester double prodrug G6788 is orally bioavailable in the rat ( F = 6%) and rhesus monkey ( F = 21%) . An alternate framework utilized a tricyclic nucleus such as in G7453, which is slightly more potent than inhibitors containing the bicyclic nucleus (IC 50 = 54 nM, ADP-induced platelet aggregation) …”

Section: Design Of Nonpeptide Antagonists For Oral Administrationmentioning

confidence: 99%

Platelet Glycoprotein IIb-IIIa Antagonists as Prototypical Integrin Blockers: Novel Parenteral and Potential Oral Antithrombotic Agents

2000

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Abstract-During the last decade, intensive efforts have been made to evaluate the role of the platelet glycoprotein (GP) IIb/IIIa complex in platelet-mediated thrombus formation. Significant efforts have also been made to design potent antagonists of this "final common pathway" of platelet aggregation to be used as novel therapeutic strategies to treat acute coronary syndromes. Although several different GP IIb/IIIa antagonists have convincingly demonstrated the usefulness of this platelet-directed therapeutic strategy, a number of lingering unsolved and sometimes misunderstood issues concerning the pharmacology and optimal clinical usefulness of these agents remain to be explored. This article reviews these issues, which include antagonist affinity, reversibility, and receptor specificity. Other issues are related to the effects of GP IIb/IIIa receptor availability, neoepitopes induced by antagonist binding with the potential to mediate thrombocytopenia, optimal methods of platelet monitoring and, perhaps ultimately, the potential therapeutic index of the oral class of GP IIb/IIIa antagonists. All of these specific issues are likely to be illuminated in the next several years, which will greatly determine the breadth of this therapeutic class. (Circulation. 1999;100:437-444.)Key Words: platelet aggregation inhibitors Ⅲ pharmacology Ⅲ angioplasty Ⅲ angina Ⅲ thrombosis E vidence that platelets play a central role in acute coronary syndromes has accumulated over the last several decades and verifies the need for more effective, yet safe, antiplatelet agents. 1 Aspirin continues to be used routinely in coronary angioplasty and to treat patients with myocardial infarction or unstable angina. Mechanistic considerations argue that a more vigorous approach to the inhibition of platelet aggregation should afford greater antithrombotic protection. Glycoprotein (GP) IIb/IIIa (␣ IIb ␤ 3 ) serves as the receptor on platelets that binds plasma-borne adhesive proteins, such as fibrinogen and von Willebrand factor (vWF), to permit platelet aggregation. 2 Aggregation is mediated by this pathway, irrespective of the agonist that stimulates platelets and irrespective of the stimulus-response-coupling pathway that is used to activate GP IIb/IIIa to aggregate platelets. Agents that block this final common pathway by blocking the binding of adhesive proteins to GP IIb-IIIa, termed GP IIb/IIIa antagonists, are currently considered the most powerful specific inhibitors of platelet participation in acute thrombosis. 3 However, the hemostatic function of platelets is also dependent on this pathway. Thus, this novel form of antiplatelet therapy comes with potential safety risks, yet the first fruits of the benefits of this therapeutic approach have begun to emerge.Various antagonists of GP IIb/IIIa are currently receiving considerable attention from the pharmaceutical industry and clinical cardiologists, and they are being studied in a variety of clinical settings. 4 -7 The first of these agents, the monoclonal antibody abciximab, has...

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“…Tetrazole-fused 1,4-benzodiazepines are known benzodiazepine receptor binders23 and glycoprotein GPIIb/IIIb antagonists 24. Toward preparing such compounds, we found that 27 , which was readily prepared from 14 by acylation with 2-azidobenzoyl chloride,25 underwent an intramolecular dipolar cycloaddition upon heating to give the hexacylic fused-tetrazole 30 ; a related approach to tetrazole-fused 1,4-benzodiazepines has been reported by Garanti 26…”

mentioning

confidence: 72%

Synthesis and Diversification of 1,2,3-Triazole-Fused 1,4-Benzodiazepine Scaffolds

Donald

Martin

2011

Org. Lett.

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A substituted heterocyclic scaffold comprising a 1,4-benzodiazepine fused with a 1,2,3-triazole ring has been synthesized and diversified via a variety of refunctionalizations. The strategy features the rapid assembly of the scaffold by combining 3-4 reactants in an efficient multicomponent assembly process, followed by an intramolecular Huisgen cycloaddition.Privileged scaffolds are uniquely suited to the preparation of molecular libraries for lead development in medicinal chemistry. 1 Such frameworks are attractive for drug discovery because of the high hit rates and the pharmacological profiles of their derivatives relative to those of other ring systems. By varying substitutents on these privileged scaffolds, one can often identify potent and selective binders for multiple biological targets from a single library. Indeed, a retrospective analysis of all known drugs reveals that nearly 25% can be traced back to a mere 41 substructures that have since been catagorized as privileged. 2

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Preparation and biological activity of novel tricyclic GPIIb/IIIa antagonists

Cited by 14 publications

References 35 publications

Solvent-Free Heterocyclic Synthesis

Solvent-Free Heterocyclic Synthesis

Platelet Glycoprotein IIb-IIIa Antagonists as Prototypical Integrin Blockers: Novel Parenteral and Potential Oral Antithrombotic Agents

Synthesis and Diversification of 1,2,3-Triazole-Fused 1,4-Benzodiazepine Scaffolds

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