phenylalanyl-prolyl-arginine and arginyl-glycyl-aspartic-acid

Peptide leads D-Phe-Pro-Arg for thrombin inhibition and Arg-Gly-Asp for antagonistic activity on fibrinogen receptor were combined in one molecule in order to produce compounds capable of acting both as thrombin inhibitors and as fibrinogen receptor antagonists. Peptide conjugate 7 possessing both leads joined by a tetraglycine linker as well as tripeptides and peptidomimetics with highly overlapped D-Phe-Pro-Arg and Arg-Gly-Asp pharmacophore groups were prepared. Conjugate 7 was found to possess antagonistic activity on fibrinogen receptor, but was unexpectedly inactive as thrombin inhibitor. Compound 9 comprising of highly integrated D-Phe-Pro-Arg and Arg-Gly-Asp pharmacophore groups was found to possess a moderate but well balanced thrombin inhibitory and fibrinogen receptor antagonistic activity.

Topics: Amino Acid Sequence; Anticoagulants; Binding Sites; Drug Design; Enzyme Inhibitors; Fibrinogen; Humans; Male; Models, Molecular; Molecular Sequence Data; Molecular Structure; Oligopeptides; Peptides; Platelet Aggregation; Receptors, Fibrinogen; Stereoisomerism; Structure-Activity Relationship; Thrombin

A novel class of potential antithrombotic compounds with moderate thrombin inhibitory and fibrinogen receptor antagonistic activity is described. Combination of anticoagulant and antiaggregatory activity in the same molecular entity is presented as a new promising approach in the search for novel antithrombotic agents.

Topics: Anticoagulants; Benzoxazines; Factor Xa Inhibitors; Fibrinogen; Fibrinolytic Agents; Models, Molecular; Molecular Mimicry; Molecular Weight; Oligopeptides; Peptides; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Receptors, Fibrinogen; Thrombin