Fused bicyclic Gly-asp β-turn mimics with potent affinity for GPIIb-IIIa. Exploration of the arginine isostere

• Published in: Bioorganic & medicinal chemistry letters Vol. 10; no. 4; pp. 385 - 389
• Main Authors: FISHER, M. J, GIESE, U, RAPP, A, RÜHTER, G, RUTERBORIES, K. J, SALL, D. J, SCARBOROUGH, R. M, SCHOTTEN, T, STENZEL, W, TOWNER, R. D, UM, S. L, UTTERBACK, B. G, HARMS, C. S, WYSS, V. L, JAKUBOWSKI, J. A, KINNICK, M. D, LINDSTROM, T. D, MCCOWAN, J. R, MEST, H.-J, MORIN, J. M, MULLANEY, J. T, PAAL, M
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 21-02-2000
• Subjects: Acetates - metabolism; Adenosine Diphosphate - pharmacology; Amidines - metabolism; Animals; Arginine - chemistry; Benzamidines - chemistry; Biological and medical sciences; Biological Availability; Blood. Blood coagulation. Reticuloendothelial system; Drug Evaluation; Enzyme-Linked Immunosorbent Assay; Fibrinogen - metabolism; Humans; Inhibitory Concentration 50; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Platelet Aggregation - drug effects; Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex - metabolism; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacokinetics; Protein Binding - drug effects; Protein Structure, Secondary; Rats; Stereoisomerism; Tetralones; Glycoprotein IIbIIIa; Rat; Peptidomimetic compound; Rodentia; Single dose; Oral administration; Non peptide compound; In vitro; Naphthalene derivatives; Biological activity; In vivo; Vertebrata; Amidine; Biological fixation; Mammalia; Area under the curve; Animal; Bicyclic compound; Affinity; Carboxamide; Aromatic compound; Antagonist; Ketoacid; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(00)00008-1

6-[4-Amidinobenzoyl]amino]-tetralone-2-acetic acid is a potent antagonist of GPIIb-IIIa. Substitution in the meta position of the benzamidine, or replacement with a heteroaryl amidine was tolerated in this series. Use of an acyl-linked 4-alkyl piperidine as an arginine isostere also provided active compounds. Compounds from this series provided substantial systemic exposure in the rat following oral administration.