Non-peptide fibrinogen receptor antagonists. 7. Design and synthesis of a potent, orally active fibrinogen receptor antagonist.
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.
Duggan
M E
ME
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Naylor-Olsen
A M
AM
Perkins
J J
JJ
Anderson
P S
PS
Chang
C T
CT
Cook
J J
JJ
Gould
R J
RJ
Ihle
N C
NC
Hartman
G D
GD
Lynch
J J
JJ
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
D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D015091:beta-Alanine; C095356:L 734217