Fibrinogen Receptor (GPIIb-IIIa) Antagonists Derived from 5,6-Bicyclic Templates. Amidinoindoles, Amidinoindazoles, and Amidinobenzofurans Containing the N-α-Sulfonamide Carboxylic Acid Function as Potent Platelet Aggregation Inhibitors
- 1 December 1997
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 40 (26), 4308-4318
- https://doi.org/10.1021/jm9704863
Abstract
A series of highly potent and specific fibrinogen receptor antagonists have been discovered and optimized through structural modification of the novel amidinoindole and benzofuran compounds, I and II. Systematic linker optimization afforded the amidinobenzofuran-containing inhibitor 29, which displayed an IC50 value of 250 nM in platelet aggregation assays. Attempts to enhance activity by modification of the beta-position of the beta-alanyl carboxylate group of 29 had only a modest effect on inhibitory activity in aggregation assays. Analogues prepared to enhance the activity by conformational restriction were also found to be equally or less potent. In contrast, modification at the alpha-position of the beta-alanyl carboxylate group resulted in the identification of extremely potent and novel amidinobenzofuran-containing derivatives 46-49. Reexamination of 5,6-bicyclic aromatic nucleus led to the further identification of amidinoindole- and amidinoindazole-containing derivatives 53-55. These analogues, 46-49 and 53-55, exhibited potent in vitro activity with IC50 values of 25-65 nM in platelet aggregation assays and an IC50 value of 2 nM in fibrinogen binding assays and demonstrated a selectivity of > 50,000-fold for GPIIb-IIIa versus the most closely related integrin, the vitronectin receptor, alpha v beta 3.Keywords
This publication has 18 references indexed in Scilit:
- Non-Peptide Glycoprotein IIb/IIIa Antagonists. 11. Design and in Vivo Evaluation of 3,4-Dihydro-1(1H)-isoquinolinone-Based Antagonists and Ethyl Ester ProdrugsJournal of Medicinal Chemistry, 1996
- Non-Peptide Fibrinogen Receptor Antagonists. 7. Design and Synthesis of a Potent, Orally Active Fibrinogen Receptor AntagonistJournal of Medicinal Chemistry, 1995
- Potent in Vitro and in Vivo Inhibitors of Platelet Aggregation Based Upon the Arg-Gly-Asp Sequence of Fibrinogen. (Aminobenzamidino)succinyl (ABAS) Series of Orally Active Fibrinogen Receptor AntagonistsJournal of Medicinal Chemistry, 1995
- Orally Active Non-Peptide Fibrinogen Receptor (GpIIb/IIIa) Antagonists: Identification of 4-[4-[4-(Aminoimino methyl)phenyl]-1-piperazinyl]-1- piperidineacetic Acid as a Long-Acting, Broad-Spectrum Antithrombotic AgentJournal of Medicinal Chemistry, 1994
- Non-Peptide Fibrinogen Receptor Antagonists. 2. Optimization of a Tyrosine Template as a Mimic for Arg-Gly-AspJournal of Medicinal Chemistry, 1994
- Template-Constrained Cyclic Peptides: Design of High-Affinity Ligands for GPIIb/IIIaJournal of the American Chemical Society, 1994
- Low molecular weight, non-peptide fibrinogen receptor antagonistsJournal of Medicinal Chemistry, 1992
- The vitronectin receptor alpha v beta 3 binds fibronectin and acts in concert with alpha 5 beta 1 in promoting cellular attachment and spreading on fibronectin.The Journal of cell biology, 1990
- Direct acting, highly mutagenic, .alpha.-hydroxy N-nitrosamines from 4-chloroindolesJournal of the American Chemical Society, 1986
- Exposure of platelet fibrinogen receptors by ADP and epinephrine.JCI Insight, 1979