Synthesis and Assessment of Antiplatelet and Antithrombotic Activity of 4-Amino-Substituted 5-Oxoproline Amides and Peptides.

Venous thromboembolism is a serious problem because it significantly increases the risk of developing vascular complications in elderly patients with obesity or immobilization, cancer, and many other diseases. Thus, there is a need to study new therapeutic strategies, including new medicinal agents for the efficient and safe correction of thrombus disorders. In this work, we have synthesized a number of new amides and peptides of 4-amino-5-oxoprolines and studied their antiplatelet and antithrombotic activity in experiments in vitro and in vivo. It has been found that the newly obtained compounds slow down the process of thrombus formation in a model of arterial and venous thrombosis, without affecting plasma hemostasis parameters. (2S,4S)-4-Amino-1-(4-fluorophenyl)-5-oxoprolyl-(S)-phenylalanine proved to be the most efficient among the studied derivatives. The results obtained indicate the advisability of further studies on 5-oxoproline derivatives in order to design pharmaceutical agents for the prevention and treatment of the consequences of thrombosis.

Pyrimidine thioethers: A novel class of antidepressant agents, endowed with anxiolytic, performance enhancing and nootropic activity.

A series of new pyrimidine thioethers, recognized as the key intermediates in the synthesis of S-DABO antivirals, were prepared and evaluated both in vivo and in silico. The purpose of this evaluation was to find novel structural analogues of the known antihypoxic drug Isothiobarbamine endowed with improved pharmacological profile. The in vivo studies led to the identification of compounds 5c, 5e, and 5f endowed with antidepressant/anxiolytic, performance enhancing, and nootropic properties. Compounds 5c and 5f were further tested in mice affected by social depression and were able to increase motor and tentative search activity compared to control groups, along with higher interaction frequency and better results in a sucrose preference test. Overall, these data suggested a better psychoemotional state of the animals, treated with compounds 5c, and 5f. Moreover, 5c and 5f exhibited minimal acute toxicity, lower than Fluoxetine hydrochloride. Molecular modelling studies finally indicated the plausible biomolecular mechanism of action of compounds 5c, 5e, and 5f, which seem to bind GABA-A, melatonin, and sigma-1 receptors. Moreover, three-dimensional structure-activity relationships enabled to define a SAR model that will be of great utility for the design of further structurally optimized compounds of the above mentioned chemotype.

Synthesis, structure, and biological activity of 4-hetaryl-2-pyrrolidones containing a pyrazole ring.

Single diastereomers of 4-hetaryl-2-pyrrolidone-3(5)-carbo- and 2-[4-hetaryl-2-pyrrolidon-1-yl]acetohydrazides were used in reactions with 2,4-pentanedione, providing (3R*,4S*)-3-, (4R*,5R*)-5-(3,5-dimethyl-1H-pyrazole-1-carbonyl)- and 1-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-oxoethyl]-4-hetaryl-2-pyrrolidones. The structures of the synthesized compounds were confirmed by spectral methods and X-ray structural analysis. Some of the obtained compounds were shown to possess nootropic and anxiolytic activity. Supplementary Information: The online version contains supplementary material available at 10.1007/s10593-022-03140-4.

Neuroprotective action of Cortexin, Cerebrolysin and Actovegin in acute or chronic brain ischemia in rats.

This study was the first to compare the neuroprotective activity of Cerebrolysin®, Actovegin® and Cortexin® in rodent models of acute and chronic brain ischemia. The neuroprotective action was evaluated in animals with acute (middle cerebral artery occlusion) or chronic (common carotid artery stenosis) brain ischemia models in male rats. Cortexin® (1 or 3 mg/kg/day), Cerebrolysin® (538 or 1614 mg/kg/day) and Actovegin® (200 mg/kg/day) were administered for 10 days. To assess the neurological and motor impairments, open field test, adhesive removal test, rotarod performance test and Morris water maze test were performed. Brain damage was assessed macro- and microscopically, and antioxidant system activity was measured in brain homogenates. In separate experiments in vitro binding of Cortexin® to a wide panel of receptors was assessed, and blood-brain barrier permeability of Cortexin® was assessed in mice in vivo. Cortexin® or Cerebrolysin® and, to a lesser extent, Actovegin® improved the recovery of neurological functions, reduced the severity of sensorimotor and cognitive impairments in rats. Cortexin® reduced the size of necrosis of brain tissue in acute ischemia, improved functioning of the antioxidant system and prevented the development of severe neurodegenerative changes in chronic ischemia model. Radioactively labeled Cortexin® crossed the blood-brain barrier in mice in vivo with concentrations equal to 6-8% of concentrations found in whole blood. During in vitro binding assay Cortexin® (10 µg/ml) demonstrated high or moderate binding to AMPA-receptors (80.1%), kainate receptors (73.5%), mGluR1 (49.0%), GABAA1 (44.0%) and mGluR5 (39.7%), which means that effects observed in vivo could be related on the glutamatergic and GABAergic actions of Cortexin®. Thus, Cortexin, 1 or 3 mg/kg, or Cerebrolysin®, 538 or 1614 mg/kg, were effective in models acute and chronic brain ischemia in rats. Cortexin® contains compounds acting on AMPA, kainate, mGluR1, GABAA1 and mGluR5 receptors in vitro, and readily crosses the blood-brain barrier in mice.

Chemistry and Hypoglycemic Activity of GPR119 Agonist ZB-16.

This article is to highlight the chemical properties and primary pharmacology of novel GPR119 agonist ZB-16 and its analogs, which were rejected during the screening. Experiments were performed in vitro (specific activity, metabolism and cell toxicity) and in vivo (hypoglycemic activity and pharmacokinetics). ZB-16 exhibits nanomolar activity (EC50 = 7.3-9.7 nM) on target receptor GPR119 in vitro associated with hypoglycemic activity in vivo. In animals with streptozotocin-nicotinamide induced type 2 diabetes mellitus (STZ-NA T2D) daily oral dose of ZB-16 (1 mg/kg) or sitagliptin (10 mg/kg) for 28 days resulted in the reduction of blood glucose levels. The effects of ZB-16 were comparable to the hypoglycemic action of sitagliptin. ZB-16 demonstrated relatively low plasma exposition, high distribution volume, mild clearance and a prolonged half-life (more than 12 h). The present study demonstrates that the targeted search for selective GPR119 receptor agonists is a well-founded approach for developing novel drugs for the therapy of T2D. Based on the combination of high in vitro activity (compared to competitor standards), a useful ADME profile, distinct hypoglycemic activity which is comparable to the efficacy of sitagliptin in rats with experimental T2D, and the acceptable pharmacokinetic profile, we recommend the ZB-16 compound for further research.

ZB-16, a Novel GPR119 Agonist, Relieves the Severity of Streptozotocin-Nicotinamide-Induced Diabetes in Rats.

GPR119 is involved in the regulation of incretin and insulin secretion, so the GPR119 agonists have been suggested as novel antidiabetic medications. The purpose of this work was to assess the influence of novel GPR119 agonist ZB-16 on the glucose utilization, insulin, and glucagon-like peptide-1 (GLP-1) secretion and the morphology of pancreas in rats with streptozotocin-nicotinamide-induced diabetes. 45 male Wistar rats were used in the study. The criteria of streptozotocin-nicotinamide-induced diabetes were blood glucose levels of 9-14 mmol/l measured in fasting conditions on the third day since administration of streptozotocin (65 mg/kg) and nicotinamide (230 mg/kg). Animals failed to reach the criteria were excluded from the experiment. The substances were administered per os once per day for 28 days. Measurements included blood glucose monitoring (every 7 days), glucose tolerance test (every 14 days), the assessment of insulin and GLP-1 levels in blood plasma (28 days after beginning), and the results of immunohistochemical staining of pancreas. It was found that ZB-16 (1 mg/kg per os, once a day) decreases the blood glucose levels under fasting conditions and improves the glucose utilization. These changes were associated with the increase in stimulated secretion of GLP-1 and insulin, accompanied by the growth of insulin-positive cells in pancreas. Thus, ZB-16 could be a promising antidiabetic drug for oral administration.