Tatyana A. Kabanova

Design, Virtual Screening, and Synthesis of Antagonists of αIIbβ3 as Antiplatelet Agents

This article describes design, virtual screening, synthesis, and biological tests of novel αIIbβ3 antagonists, which inhibit platelet aggregation. Two types of αIIbβ3 antagonists were developed: those binding either closed or open form of the protein. At the first step, available experimental data were used to build QSAR models and ligand- and structure-based pharmacophore models and to select the most appropriate tool for ligand-to-protein docking. Virtual screening of publicly available databases (BioinfoDB, ZINC, Enamine data sets) with developed models resulted in no hits. Therefore, small focused libraries for two types of ligands were prepared on the basis of pharmacophore models. Their screening resulted in four potential ligands for open form of αIIbβ3 and four ligands for its closed form followed by their synthesis and in vitro tests. Experimental measurements of affinity for αIIbβ3 and ability to inhibit ADP-induced platelet aggregation (IC50) showed that two designed ligands for the open form 4c and 4d (IC50 = 6.2 nM and 25 nM, respectively) and one for the closed form 12b (IC50 = 11 nM) were more potent than commercial antithrombotic Tirofiban (IC50 = 32 nM).

Synthesis, biological evaluation, X-ray molecular structure and molecular docking studies of RGD mimetics containing 6-amino-2,3-dihydroisoindolin-1-one fragment as ligands of integrin αIIbβ3

A series of novel RGD mimetics containing phthalimidine fragment was designed and synthesized. Their antiaggregative activity determined by Borns method was shown to be due to inhibition of fibrinogen binding to αIIbβ₃. Molecular docking of RGD mimetics to αIIbβ₃ receptor showed the key interactions in this complex, and also some correlations have been observed between values of biological activity and docking scores. The single crystal X-ray data were obtained for five mimetics.

Synthesis, biological evaluation and molecular docking studies of 2-piperazin-1-yl-quinazolines as platelet aggregation inhibitors and ligands of integrin αIIbβ3.

A series of 2-piperazin-1-yl-quinazolines were synthesized and evaluated for their antiaggregative activity. The synthesized small molecule compounds have potently inhibited platelet aggregation in vitro and blocked FITC-Fg binding to αIIbβ3 integrin in a suspension of washed human platelets. The key αIIbβ3 protein-ligand interactions were determined in docking experiments and some correlations have been observed between values of the affinity and docking scores.

Derivatives of 1,2,3,4-tetrahydroisoquinoline-7-carboxylic Acid as Novel Fibrinogen Receptor Antagonists

It has been proposed a novel method for obtaining of 1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid as Arg-mimetic within the framework of search for novel fibrinogen receptor antagonists. New alpha (IIb)beta(3) antagonists were prepared on a base of 1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid. Their high antiaggregatory activities in a human platelet rich plasma and ability to block FITC-Fg binding to alpha (IIb)beta(3) on washed human platelets were estimated.

Novel fibrinogen receptor antagonists--RGDF mimetics, 4-(1,2,3,4-tetrahydro-isoquinoline-7-yl)amino-4-oxo-butyric acid derivatives.

Two novel RGDF mimetics were synthesized with the use of 4-(1,2,3,4-tetrahydro-isoquinoline-7-yl)amino-4-oxo-butyric acid as a new surrogate of Arg-Gly motif. The synthesized compounds have demonstrated a high potency to inhibit platelet aggregation in vitro and to block FITC-Fg binding to alphaIIbbeta3 on washed human platelets.

Derivatives of tetrahydroisoquinoline: Synthesis and initial evaluation of novel non-peptide antagonists of the αIIbβ3-integrin

The novel RGDF mimetics were synthesized with the use of 4-(1,2,3,4-tetrahydroisoquinoline-7-yl)amino-4-oxobutyric or 5-(1,2,3,4-tetrahydroisoquinoline-7-yl)amino-5-oxopentanoic acids as a surrogate of Arg-Gly motif. The synthesized compounds have demonstrated a high potency to inhibit platelet aggregation in vitro and to block FITC-Fg binding to alpha(IIb)beta(3) on washed human platelets.

RGD mimetics containing phthalimidine fragment as novel ligands of fibrinogen receptor.

The novel RGD mimetics with phthalimidine central fragment were synthesized with the use of 4-piperidine-4-yl-butyric, 4-piperidine-4-yl-benzoic, 4-piperazine-4-yl-benzoic and 1,2,3,4-tetrahydroisoquinoline-7-carboxylic acids as surrogates of Arg motif. The synthesized compounds potently inhibited platelet aggregation in vitro and blocked FITC-Fg binding to α(IIb)β(3) integrin in a suspension of washed human platelets. The key α(IIb)β(3) protein-ligand interactions were determined in docking experiments.

Synthesis and antiaggregative activity of a new RGDF mimetic

Abstractm-[4-Oxo-4-(piperazin-1-yl)butyrylamino)benzoyl-D,L-β-(3,4-methylenedioxyphenyl)-β-alanine, a new mimetic of the peptide RGDF, was synthesized. This compound inhibited ADP-induced platelet aggregation in human blood plasma enriched with platelets with IC50 = 3.5 × 10–8 M.

Synthesis and Antiaggregant Activity of N-[4-Oxo-4-(4-ethoxycarbonylpiperazin-1-yl)butyryl]glicyl-D,L-β-phenyl-β-Alanine Ethyl Ester

In the final stage of thrombocyte aggregation, fibrinogen binds to a glycoprotein complex (GP IIb IIIa) on the surface of activated thrombocytes. At present, the attention of researchers is mostly devoted to elucidating the role of selective antagonists of the GP IIb IIIa fibrinogen receptors in preventing thrombosis. Compounds possessing antiaggregant activity, based on the RGD peptide sequence Arg-Gly-Asp (the fragment of fibrinogen molecule responsible for the binding to receptor), compete with fibrinogen for the binding sites on thrombocytes and prevent the latter from aggregation [1]. By now, there is a large number of GP IIb IIIa antagonists, including nonpeptide inhibitors. Most of these compounds reproduce the recognition RGD peptide sequence [2, 3]. Recently [4, 5], we have synthesized an RGDF peptide mimetic 4-oxo-4-(4-piperazin-1-yl)butyryl-glicyl-D,Lphenyl-alanine (I) possessing pronounced antiaggregant properties in vitro and characterized by high affinity to fibrinogen receptors.

Synthesis and antiaggregative activity of derivatives of 3-aminopiperidine-2,6-diones and 3-aminopyrrolidine-2,5-diones

The search for new antithrombic and antiaggregative agents possessing high activity and low toxicity is a currently important task of pharmaceutical chemistry [1]. A large number of potential antiaggregants have been described in the literature by now, which can be divided into several groups according to the mechanism of their action. In one group, the mechanism is related to the arachidonic acid metabolism. Other groups are characterized by influence upon the ADPdependent aggregation pathway or inhibition of the thromboeyte aggregation factor [2]. However, there are many compounds of different structures, also possessing the antiaggregative properties, whose mechanism of action is still unclear. A group of potential antiaggregants includes pyridyloxazoles and their 4,5-dihydro analogs [3], imidazoquinolin-2-one [4], and piperidine-3-carboxamides [5]. Previously we have reported that antiaggregative activity is also observed in a group of derivatives of 3-aminopiperidine-2,6-diones [6]. In order to find new effective antiaggregants among these compounds and their analogs-3-aminopyrrolidine-2,5-diones, we have synthesized a series of compounds ( I -XII I ) and studied their properties;