Effect of some biologically interesting substituted tetrahydro-1,4-oxazines on drug metabolising enzymes and on inflammation

The effect on hepatic drug metabolising enzymes was evaluated for three representative structures (1, 2 and 3) that were selected from a series of substituted oxazine derivatives designed to possess particular pharmacological properties such as analgesic, antioxidant and hypolipidemic activity. In addition, since xenobiotic metabolism, reactive oxygen and nitrogen species, atherosclerosis and inflammation are interrelated and mutually affected, the effects of (2) and (3) on acute inflammation in vivo and lipoxygenase activity in vitro were also investigated. It was found that treatment of rats with (1) caused induction of cytochrome P450, enhancement of the metabolism of aminopyrine in vitro and of zoxazolamine and hexobarbital in vivo. Compound (2) appeared to induce particularly erythromycin N-demethylation, while (3), a nitric ester, reduced the catalytically active cytochrome P450, although it increased the metabolism of specific cytochrome P450 substrates, i.e. 4-nitrophenol and erythromycin. Compounds (2) and (3), with strong hypolipidemic and antioxidant properties, reduced acute inflammatory response in two inflammation models and inhibited lipoxygenase activity in vitro. These results are helpful in optimising the biological profile as well as the potential applications of substituted oxazines. © 2005 Bentham Science Publishers Ltd

Novel compounds designed as antistress agents

Agents against biologic stress were designed, containing GABA esterified with lorazepam and amidated with (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2- carboxylic acid (5) or3,5-di-tert-butyl-4-hydroxybenzoic acid (6). Compounds 5 and 6 inhibited lipid peroxidation, IC50 1.1 and 24 μM. Oxidative damage accompanied stress, 5 and 6 reduced radical attack, uropepsinogen, and morphological changes. Stress increased drug metabolism. Treatment with 5 reduced cytochrome P450 and N-demethylation of erythromycin, 35 and 40%. Compounds 5 and 6 decreased lipidemic indices of hyperlipidemic rats 40-63%. ©2009 American Chemical Society

Lipid-lowering (hetero)aromatic tetrahydro-1,4-oxazine derivatives with antioxidant and squalene synthase inhibitory activity

A number of newly synthesized 2-[4-(hetero)aromatic]phenyl-2-hydroxy- tetrahydro-1,4-oxazine derivatives were found to inhibit lipid peroxidation (IC50 of the most potent was 20 μM) as well as rat squalene synthase (IC50 for most between 1-10 μM). Antidyslipidemic action was demonstrated in vivo: the most active compound decreased triglycerides, total cholesterol, and LDL-cholesterol of hyperlipidemic rats by 64, 67, and 82%, respectively, at 56 μmol/kg (ip). Most of the novel compounds are more active than the structurally related and reference biphenyl-morpholine, pointing to useful structural approaches for the design of antiatherosclerotic agents. © 2008 American Chemical Society

Stress and active oxygen species - Effect of α-tocopherol on stress response

Stress is implicated in the pathogenesis of numerous disorders such as cardiovascular diseases or neurodegeneration. The extensive overlap between diseases attributed to stress and oxidative damage is indicative of their potential relationship. We hereby study the influence of α-tocopherol (α-toc) on the development of stress biomarkers (morphological and biochemical), on specific biomarkers of radical insult (lipid peroxidation, oxidized proteins, or glutathione content in brain and liver), as well as on drug metabolism. In our experimental protocol two groups of female rats are exposed to stress conditions, i.e. cold plus starvation. Before stress and during its application one group is treated with α-toc for 20 d (0.42 mmol/kg per os, once daily). Our results indicate that oxidative damage accompanies the development of stress, while treatment with α-toc completely prevents stress-induced radical attack and reduces stress indices like plasma corticosterone, uropepsinogen, and morphological changes. It is found that stress increases the drug metabolic potential of the liver (total P450, CYP2E1, or CYP3A1 activity). Administration of α-toc, in combination with stress, further increases erythromycin N-demethylation (CYP3A1) compared to stress control, while 4-nitrophenol hydroxylation (CYP2E1) is not affected significantly. © 2005 WILEY-VCH Verlag GmbH & Co. KGaA

Design and study of some novel ibuprofen derivatives with potential nootropic and neuroprotective properties

Six novel ibuprofen derivatives and related structures, incorporating a proline moiety and designed for neurodegenerative disorders, are studied. They possess anti-inflammatory properties and three of them inhibited lipoxygenase. One compound was found to inhibit cyclooxygenase (COX)-2 production in spleenocytes from arthritic rats. The HS-containing compounds are potent antioxidants and one of them protected against glutathione loss after cerebral ischemia/reperfusion. They demonstrated lipid-lowering ability and seem to acquire low gastrointestinal toxicity. Acetylcholinesterase inhibitory activity, found in two of these compounds, may be an asset to their actions. © 2006 Elsevier Ltd. All rights reserved

EP2306 [2-(4-biphenyl)-4-methyl-octahydro-1,4-benzoxazin-2-ol, hydrobromide], a novel squalene synthase inhibitor, reduces atherosclerosis in the cholesterol-fed rabbit

EP2306 [2-(4-biphenyl)-4-methyl-octahydro-1,4-benzoxazin-2-ol, hydrobromide] inhibits squalene synthase and lipid biosynthesis and possesses antioxidant properties. We hypothesized that EP2306 can effectively modify circulating lipids and reduce atherosclerosis in the cholesterol-fed rabbit. Animals were fed a high-cholesterol diet for 4 weeks followed by 4 (phase 1 and 2) or 12 weeks (phase 3) of drug treatment while on high-cholesterol diet. In phase 1, the dose-effect relationship of EP2306 on lipids and atherosclerosis was established, and its most effective dose was determined (2 mg/kg). This dose reduced significantly total cholesterol (512 ± 96 mg/dl before versus 320 ± 124 mg/dl after treatment, p < 0.05) and atherosclerotic lesions compared with control animals. In phase 2, the effects of 2 mg/kg EP2306, 2.5 mg/kg simvastatin, and their combination were assessed. Although no significant effect on lipid parameters was observed, there was a significant reduction (35 ± 5%, p < 0.05) of atherosclerotic lesions in animals treated with EP2306, a similar reduction with simvastatin, and a further reduction (48 ± 7%, p < 0.05) when the two agents were combined. In animals treated for 12 weeks with the drugs (phase 3), only EP2306 significantly reduced atherosclerotic lesions by more than 50%, whereas simvastatin alone or in combination with EP2306 had no effect. Treatment with EP2306 did not adversely affect liver transaminases or cause any histopathological changes on various organs of the animals. In conclusion, we have shown that EP2306 inhibits atherosclerosis in vivo, indicating potential as a novel therapeutic agent for coronary artery disease and other atherosclerosis-related disorders. Copyright © 2007 by The American Society for Pharmacology and Experimental Therapeutics

Antiatherosclerotic properties of EP2302, A novel squalene synthase inhibitor, in the cholesterol-fed rabbit

EP2302 is a novel nitric oxide donor compound that inhibits squalene synthase. We hypothesized that EP2302 can reduce atherosclerosis in the cholesterol-fed rabbit atherosclerosis model. Animals were fed a high-cholesterol (HC) diet for 4 weeks. Animals subsequently received drug or placebo for 4 (n = 15) or 12 weeks (n = 15) while on HC diet. A third group (n = 16) received drug or placebo for 4 weeks while on regular diet (regression group). No significant differences were observed in circulating lipids among any of the treatment groups at each time point during HC intake. The perimeter and area of the ascending aorta covered by lesions were significantly decreased in animals treated with 2 mg/kg EP2302 for 4 weeks (44% and 42% reduction, respectively). Moreover, a significant decrease in the perimeter of the ascending and descending aorta covered by lesions was observed in animals treated with 2 mg/kg EP2302 for 12 weeks (73% and 44% reduction, respectively) as well as in the regression group (61% and 65% reduction, respectively). Treatment with EP2302 did not cause any toxicity in animal vital organs. We have shown that EP2302 inhibits atherosclerosis in the cholesterol-fed rabbit and therefore may serve as a candidate drug to be tested in humans for atherosclerosis-related disorders. © 2008 by Lippincott Williams & Wilkins

Synthesis and pharmacochemical study of novel polyfunctional molecules combining anti-inflammatory, antioxidant, and hypocholesterolemic properties

We have designed and synthesized a series of novel molecules having a residue of a classical NSAID and an antioxidant moiety, both attached through amide bonds to a known nootropic structure, an l-proline, trans-4-hydroxy-l- proline or dl-pipecolinic acid residue. The compounds were found to retain anti-inflammatory and antioxidant activities, to acquire hypocholesterolemic action, and to possess a greatly reduced gastrointestinal toxicity. The novel molecules could find useful applications, among others, in slowing the progression or delaying the onset of neurodegenerative diseases. © 2005 Elsevier Ltd. All rights reserved

Synthesis and pharmacological evaluation of amide conjugates of NSAIDs with L-cysteine ethyl ester, combining potent antiinflammatory and antioxidant properties with significantly reduced gastrointestinal toxicity

The synthesis and pharmacological evaluation of a series of amide derivatives of NSAIDs with L-cysteine ethyl ester is described. The novel derivatives are potent antiinflammatory, antioxidant and hypocholesterolemic- hypolipidemic agents, while they demonstrate considerably reduced gastrointestinal toxicity. This molecular modification may offer a general route to safer antiinflammatory agents, potentially suitable for chronic use in conditions such as neurodegenerative disorders. © 2004 Elsevier Ltd. All rights reserved