Abstract
The integrin receptor recognition sequence Arg-Gly-Asp was successfully used as a template from which to develop a series of potent, selective, orally active, peptide-based fibrinogen receptor antagonists with a long duration of action. Simple modifications centered on the Arg and Gly residues quickly led to a modified peptide (1) with significantly enhanced ability to inhibit in vitro platelet aggregation. Substitution of the guanidino group in 1 by piperidine provided 3, which showed not only a further increase in potency but also a modest degree of oral efficacy. Finally, exploration of the nature of the C-terminal amino acid, with respect to its side-chain functionality and the carboxy terminus, yielded a group of molecules that showed excellent in vitro potency for inhibiting platelet aggregation, excellent integrin selectivity, a high level of oral efficacy, and an extended duration of action.
MeSH terms
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Administration, Oral
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Animals
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Blood Platelets / drug effects
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Cell Adhesion / drug effects
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Dogs
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Female
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Humans
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In Vitro Techniques
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Male
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Oligopeptides* / administration & dosage
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Oligopeptides* / chemical synthesis
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Oligopeptides* / metabolism
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Oligopeptides* / pharmacology
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Piperidines* / administration & dosage
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Piperidines* / chemical synthesis
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Piperidines* / metabolism
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Piperidines* / pharmacology
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Platelet Activation
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Platelet Aggregation / drug effects
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Platelet Aggregation Inhibitors* / administration & dosage
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Platelet Aggregation Inhibitors* / chemical synthesis
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Platelet Aggregation Inhibitors* / metabolism
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Platelet Aggregation Inhibitors* / pharmacology
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Platelet Glycoprotein GPIIb-IIIa Complex / antagonists & inhibitors*
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Structure-Activity Relationship
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Umbilical Veins / cytology
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Umbilical Veins / drug effects
Substances
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Oligopeptides
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Piperidines
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Platelet Aggregation Inhibitors
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Platelet Glycoprotein GPIIb-IIIa Complex