GPIIb/IIIa Antagonists as Novel Antithrombotic Drugs

Vasko, J.; Koster, Paul F.; Valocik, Richard E.

doi:10.1007/978-1-4615-2466-3_13

Cited by 6 publications

(8 citation statements)

References 50 publications

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“…It is important to initially review how the two potent intravenous GPIIb/IIIa antagonists SK&F 106760 and SK&F 107260 were discovered. The role of GPIIb/lIIa antagonists in the prevention of thrombosis has been amply reviewed (Nichols et al , 1994a. Since chronic oral administration of GPIIb/IIla antagonists could, in principal, address leading causes of death in the United States (Gunby 1992) intense interest has developed over the discovery of orally active GPIIb/IIIa antagonists.…”

Section: Introduction: Peptide Drugs Vs Nonpeptide Drugsmentioning

confidence: 99%

Chemical Approaches to Improve the Oral Bioavailability of Peptidergic Molecules

Samanen

Wilson

Smith

et al. 1996

Journal of Pharmacy and Pharmacology

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This review discusses both tools and strategies that may be employed as approaches towards the pursuit of orally active compounds from peptidergic molecules. Besides providing a review of these subjects, this paper provides an example of how these were utilized in a research programme at SmithKline Beecham involving the development of orally active GPIIb/IIIa antagonists. The tools for studying oral drug absorption in-vitro include variants of the Ussing chamber which utilize either intestinal tissues or cultured epithelial cells that permit the measurement of intestinal permeability. Example absorption studies that are described are mannitol, cephalexin, the growth hormone-releasing peptide SK&F 110679 and two GPIIb/IIIa antagonist peptides SK&F 106760 and SK&F 107260. With the exception of cephalexin, these compounds cross the intestine by passive paracellular diffusion. Cephalexin, on the other hand, crosses the intestine via the oligopeptide transporter. Structure-transport studies are reviewed for this transporter. The tools for studying oral drug absorption in-vivo involve animals bearing in-dwelling intestinal or portal vein catheters. A study of the segmental absorption of SK&F 106760 is provided. The review concludes with two chemical strategies that may be taken towards the enhancement of oral bioavailability of peptidergic molecules. The first strategy involves the chemical modification of peptides which enhance intestinal permeability, specifically the modification of amide bonds. The second strategy involves the design of compounds bearing nonpeptide templates, which are more amenable to the discovery of compounds with oral activity, from peptide pharmacophore models. An example is given regarding the discovery of SB 208651, a potent orally active GPIIb/IIIa antagonist, designed from the peptides SK&F 106760 and SK&F 107260.

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Section: Introduction: Peptide Drugs Vs Nonpeptide Drugsmentioning

confidence: 99%

Chemical Approaches to Improve the Oral Bioavailability of Peptidergic Molecules

Samanen

Wilson

Smith

et al. 1996

Journal of Pharmacy and Pharmacology

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“…As for a IIb b 3 antagonists, a study of RGD-containing tri-and tetrapeptides led to the discovery of cyclic RGD-containinng peptides, e.g., SK&F 106760. 7) Although SK&F 106760 displayed potent in vivo antiaggregatory activity following intravenous infusion, 8) peptidic antagonists are generally thought to lack the activity and duration after oral administration. As a result of earnest studies of nonpeptidic RGD mimetics, several orally active a IIb b 3 antagonists were discoverd.…”

mentioning

confidence: 99%

Novel Malonamide Derivatives as .ALPHA.v.BETA.3 Antagonists. Syntheses and Evaluation of 3-(3-Indolin-1-yl-3-Oxopropanoyl)aminopropanoic Acids on Vitronectin Interaction with .ALPHA.v.BETA.3.

Nagashima¹,

Akamatsu²,

Kawaminami³

et al. 2001

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…SB-214857 is a potent GP IIb/IIIa antagonist and, as a consequence, inhibits platelet aggregation . It has been proposed for clinical trials for the prevention of secondary thrombotic events such as heart attack and stroke.…”

mentioning

confidence: 99%

“…SB-214857 is a potent GP IIb/IIIa antagonist and, as a consequence, inhibits platelet aggregation. 1 It has been proposed for clinical trials for the prevention of secondary thrombotic events such as heart attack and stroke. Initial supplies of SB-214857 for toxicological testing were made using the medicinal chemistry route 2 which is summarised in Scheme 1.…”

mentioning

confidence: 99%

A New and Convergent Synthesis of (2S)-7-(4,4‘-Bipiperidinylcarbonyl)-2,3,4,5- tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic Acid Using a Palladium-Catalysed Aminocarbonylation Reaction

Etridge¹,

Hayes²,

Walsgrove³

et al. 1998

Org. Process Res. Dev.

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GPIIb/IIIa Antagonists as Novel Antithrombotic Drugs

Cited by 6 publications

References 50 publications

Chemical Approaches to Improve the Oral Bioavailability of Peptidergic Molecules

Chemical Approaches to Improve the Oral Bioavailability of Peptidergic Molecules

Novel Malonamide Derivatives as .ALPHA.v.BETA.3 Antagonists. Syntheses and Evaluation of 3-(3-Indolin-1-yl-3-Oxopropanoyl)aminopropanoic Acids on Vitronectin Interaction with .ALPHA.v.BETA.3.

A New and Convergent Synthesis of (2S)-7-(4,4‘-Bipiperidinylcarbonyl)-2,3,4,5- tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic Acid Using a Palladium-Catalysed Aminocarbonylation Reaction

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