Non-Peptide Glycoprotein IIb/IIIa Inhibitors. 17. Design and Synthesis of Orally Active, Long-Acting Non-Peptide Fibrinogen Receptor Antagonists

The synthesis and pharmacological evaluation of 5 (L-738,167), a potent, selective non-peptide fibrinogen receptor antagonist is reported. Compound 5 inhibited the aggregation of human gel-filtered platelets with an IC50 value of 8 nM and was found to be >33000-fold less effective at inhibiting t...

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Published in:	Journal of medicinal chemistry Vol. 40; no. 12; pp. 1779 - 1788
Main Authors:	Askew, Benny C, Bednar, Rodney A, Bednar, Bohumil, Claremon, David A, Cook, Jacquelynn J, McIntyre, Charles J, Hunt, Cecila A, Gould, Robert J, Lynch, Robert J, Lynch, Joseph J, Gaul, Stanley L, Stranieri, Maria T, Sitko, Gary R, Holahan, Marie A, Glass, Joan D, Hamill, Terrence, Gorham, Lynn M, Prueksaritanont, Thomayant, Baldwin, John J, Hartman, George D
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 06-06-1997
Subjects:	Adenosine Diphosphate - pharmacology Animals Azepines - chemical synthesis Azepines - metabolism Azepines - pharmacology Biological and medical sciences Blood Platelets - drug effects Blood Platelets - metabolism Blood. Blood coagulation. Reticuloendothelial system Collagen - pharmacology Dogs Endothelium, Vascular - drug effects Endothelium, Vascular - metabolism Fibrinogen - metabolism Fibrinolytic Agents - chemical synthesis Fibrinolytic Agents - chemistry Fibronectins - metabolism Humans Medical sciences Molecular Structure Pharmacology. Drug treatments Platelet Aggregation Inhibitors - chemical synthesis Platelet Aggregation Inhibitors - pharmacology Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors Platelet Glycoprotein GPIIb-IIIa Complex - metabolism Structure-Activity Relationship Sulfonamides - chemical synthesis Sulfonamides - metabolism Sulfonamides - pharmacology Vitronectin - metabolism Angular nitrogen heterocycle Lactam Non peptide compound Vitronectin Anticoagulant Fibronectin Ex vivo Fibrinogen Piperidine derivatives Bicyclic compound Antagonist Chemical synthesis Dog Biological receptor Human Fissipedia Carnivora Glycoprotein IIbIIIa Oral administration In vitro Biological activity Antiplatelet agent α-Aminoacid Vertebrata Mammalia Animal
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Summary:	The synthesis and pharmacological evaluation of 5 (L-738,167), a potent, selective non-peptide fibrinogen receptor antagonist is reported. Compound 5 inhibited the aggregation of human gel-filtered platelets with an IC50 value of 8 nM and was found to be >33000-fold less effective at inhibiting the attachment of human endothelial cells to fibrinogen, fibronectin, and vitronectin than it was at inhibiting platelet aggregation. Ex vivo platelet aggregation was inhibited by >85% 24 h after the oral administration of 5 to dogs at 100 μg/kg. The extended pharmacodynamic profile exhibited by 5 appears to be a consequence of its high-affinity binding to GPIIb/IIIa on circulating platelets and suggests that 5 is suitable for once-a-day dosing.
Bibliography:	Abstract published in Advance ACS Abstracts, May 15, 1997. istex:42A36D0122F2C93BB6FDD694BD7A08A33F189D7C ark:/67375/TPS-2JRZ4DMN-H ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm9608117