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Non-peptide fibrinogen receptor antagonists. 7. Design and synthesis of a potent, orally active fibrinogen receptor antagonist. 1995

M E Duggan, and A M Naylor-Olsen, and J J Perkins, and P S Anderson, and C T Chang, and J J Cook, and R J Gould, and N C Ihle, and G D Hartman, and J J Lynch
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.

The design, synthesis, and pharmacological evaluation of L-734,217, a potent, low-molecular weight, orally active fibrinogen receptor antagonist, is reported. A strategy for producing low-molecular weight inhibitors from the peptide c-[(Ac)CRGDC] A, previously reported from these laboratories, is outlined. This strategy combines a retrodesign analysis of the conformationally defined cyclic peptide A with stereochemical information present in the arginine-glycine-aspartic acid (RGD) tripeptide sequence, culminating with the discovery of L-734,217. L-734,217 inhibited the aggregation of human, dog, and chimpanzee platelets at concentrations below 100 nM and was found to be > 15000-fold less effective at inhibiting the attachment of human umbilical vein endothelial cells to fibrinogen, fibronectin, and vitronectin than it was at inhibiting the aggregation of platelets. L-734,217 showed significant ex vivo antiplatelet activity following oral administration in dogs and chimpanzees at doses of 1.0 and 2.0 mg/kg, respectively, and has been selected as a clinical candidate for development as an antithrombotic agent.

UI MeSH Term Description Entries
D008969 Molecular Sequence Data Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories. Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D009682 Magnetic Resonance Spectroscopy Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (MAGNETIC RESONANCE IMAGING). In Vivo NMR Spectroscopy,MR Spectroscopy,Magnetic Resonance,NMR Spectroscopy,NMR Spectroscopy, In Vivo,Nuclear Magnetic Resonance,Spectroscopy, Magnetic Resonance,Spectroscopy, NMR,Spectroscopy, Nuclear Magnetic Resonance,Magnetic Resonance Spectroscopies,Magnetic Resonance, Nuclear,NMR Spectroscopies,Resonance Spectroscopy, Magnetic,Resonance, Magnetic,Resonance, Nuclear Magnetic,Spectroscopies, NMR,Spectroscopy, MR
D010880 Piperidines A family of hexahydropyridines.
D010974 Platelet Aggregation The attachment of PLATELETS to one another. This clumping together can be induced by a number of agents (e.g., THROMBIN; COLLAGEN) and is part of the mechanism leading to the formation of a THROMBUS. Aggregation, Platelet
D010975 Platelet Aggregation Inhibitors Drugs or agents which antagonize or impair any mechanism leading to blood platelet aggregation, whether during the phases of activation and shape change or following the dense-granule release reaction and stimulation of the prostaglandin-thromboxane system. Antiaggregants, Platelet,Antiplatelet Agent,Antiplatelet Agents,Antiplatelet Drug,Blood Platelet Aggregation Inhibitor,Blood Platelet Antagonist,Blood Platelet Antiaggregant,PAR-1 Antagonists,Platelet Aggregation Inhibitor,Platelet Antagonist,Platelet Antagonists,Platelet Antiaggregant,Platelet Antiaggregants,Platelet Inhibitor,Protease-Activated Receptor-1 Antagonists,Antiplatelet Drugs,Blood Platelet Aggregation Inhibitors,Blood Platelet Antagonists,Blood Platelet Antiaggregants,Platelet Inhibitors,Agent, Antiplatelet,Aggregation Inhibitor, Platelet,Antagonist, Blood Platelet,Antagonist, Platelet,Antiaggregant, Blood Platelet,Antiaggregant, Platelet,Drug, Antiplatelet,Inhibitor, Platelet,Inhibitor, Platelet Aggregation,PAR 1 Antagonists,Platelet Antagonist, Blood,Platelet Antiaggregant, Blood,Protease Activated Receptor 1 Antagonists
D010980 Platelet Membrane Glycoproteins Surface glycoproteins on platelets which have a key role in hemostasis and thrombosis such as platelet adhesion and aggregation. Many of these are receptors. PM-GP,Platelet Glycoprotein,Platelet Membrane Glycoprotein,PM-GPs,Platelet Glycoproteins,Glycoprotein, Platelet,Glycoprotein, Platelet Membrane,Glycoproteins, Platelet,Glycoproteins, Platelet Membrane,Membrane Glycoprotein, Platelet,Membrane Glycoproteins, Platelet,PM GP
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D002679 Pan troglodytes The common chimpanzee, a species of the genus Pan, family HOMINIDAE. It lives in Africa, primarily in the tropical rainforests. There are a number of recognized subspecies. Chimpanzee,Chimpanzee troglodytes,Chimpanzee troglodyte,Chimpanzees,Pan troglodyte,troglodyte, Pan,troglodytes, Chimpanzee
D004285 Dogs The domestic dog, Canis familiaris, comprising about 400 breeds, of the carnivore family CANIDAE. They are worldwide in distribution and live in association with people. (Walker's Mammals of the World, 5th ed, p1065) Canis familiaris,Dog
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man

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