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

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.

Organocatalysed Asymmetric β‐Amination and Multicomponent syn‐Selective Diamination of α,β‐Unsaturated Aldehydes

“…This represents an easy and practical method to obtain protected optically active b-amino aldehydes and alcohols in good yields and enantioselectivities. These products represent a common motif in bioactive peptidomimics, for example, fibrinogen receptor antagonists, [12] which have promising potentials as leads in many pharmacological studies.…”

Orally Active Isoxazoline Glycoprotein IIb/IIIa Antagonists with Extended Duration of Action

“…19 The use of N-R-substituted diaminopropionates in other series of GPIIb/IIIa antagonists has been recently reported. [23][24][25][26][27][28][29][30][31] The use of R-sulfonamide substituents in GPIIb/IIIa antagonists containing piperidine Arg replacements has led to antiplatelet agents with extended (g8 h) duration of action. [26][27][28][29] In other GPIIb/IIIa antagonists featuring heterocyclic amidines as Arg mimics, prolonged plasma levels of active species were not demonstrated.…”

A New Approach to 2,3-Disubstituted Benzo[b]furans from o-Alkynylphenols via 5-endo-dig-Iodocyclisation/Palladium-Catalysed Reactions

“…Benzo [b]furan derivatives are important because of their occurrence in nature and their physiological properties. 1 For example, they are active as inhibitors of 5-lipoxygenase, 2 as antagonists of the angiotensin II receptor, 3 as blood coagulation factor Xa inhibitors, 4 as ligands of adenosine A 1 receptor, 5 as potent platelet aggregation inhibitors 6 and as smooth muscle contractants. 7 Benzo[b]furans with a carbamoyl group have been synthesised and evaluated for rat and human testosterone 5areductase inhibitory activities in vitro.…”