title: Non-peptide fibrinogen receptor antagonists. 7. Design and synthesis of a potent, orally active fibrinogen receptor antagonist.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Duggan
authors.forename: A M
authors.initials: AM
authors.lastname: Naylor-Olsen
authors.forename: J J
authors.initials: JJ
authors.lastname: Perkins
authors.forename: P S
authors.initials: PS
authors.lastname: Anderson
authors.forename: C T
authors.initials: CT
authors.lastname: Chang
authors.forename: J J
authors.initials: JJ
authors.lastname: Cook
authors.forename: R J
authors.initials: RJ
authors.lastname: Gould
authors.forename: N C
authors.initials: NC
authors.lastname: Ihle
authors.forename: G D
authors.initials: GD
authors.lastname: Hartman
authors.forename: J J
authors.initials: JJ
authors.lastname: Lynch
mesh_terms: D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D004285:Dogs; D015195:Drug Design; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D002679:Pan troglodytes; D010880:Piperidines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D015091:beta-Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D015091:beta-Alanine; C095356:L 734217