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1.
Molecules ; 25(1)2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31861583

RESUMO

Inflammation and oxidative stress are involved in cardiovascular diseases. Nitrogen monoxide participates in the regulation of endothelial processes. Thus, derivatives of classic nonsteroidal anti-inflammatory drugs (NSAIDs), trolox or cinnamic acids esterified with 2-(nitrooxy)ethanol were designed and studied. It was found that the nitrogen monoxide (NO) releasing activity was comparable to that of S-nitroso-N-acetylpenicillamine. The nitrooxy derivatives decreased potently lipid indices in the plasma of hyperlipidaemic rats (30-85%). All compounds presented increased anti-inflammatory activity in vivo, inhibiting carrageenan-induced rat paw oedema as high as 76%, up to six times higher than that of the parent acids. Lipoxygenase inhibitory activity was significant for most of them, although the parent molecules exerted a minor effect (IC50 > 0.2 mM). Those compounds incorporating an antioxidant structure inhibited rat microsomal membrane lipid peroxidation strongly and possessed radical scavenging activity. These results indicated that the described compounds could act at different targets in multifactorial diseases, further limiting the possible adverse effects of drug combinations.

2.
Molecules ; 24(18)2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505754

RESUMO

Novel derivatives of some non steroidal anti-inflammatory drugs, as well as of the antioxidants α-lipoic acid, trolox and (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid with lorazepam were synthesised by a straightforward method at satisfactory to high yields (40%-93%). All the tested derivatives strongly decreased lipidemic indices in rat plasma after Triton induced hyperlipidaemia. They also reduced acute inflammation and a number of them demonstrated lipoxygenase inhibitory activity. Those compounds acquiring antioxidant moiety were inhibitors of lipid peroxidation and radical scavengers. Therefore, the synthesised compounds may add to the current knowledge about multifunctional agents acting against various disorders implicating inflammation, dyslipidaemia and oxidative stress.


Assuntos
Hiperlipidemias/tratamento farmacológico , Inflamação/tratamento farmacológico , Lorazepam/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Acrilatos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Carragenina/química , Carragenina/farmacologia , Cromanos/química , Cromanos/farmacologia , Humanos , Hiperlipidemias/patologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Inibidores de Lipoxigenase/farmacologia , Lorazepam/análogos & derivados , Ratos , Ácido Tióctico/análogos & derivados , Ácido Tióctico/farmacologia
3.
Curr Top Med Chem ; 19(4): 276-291, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30706817

RESUMO

BACKGROUND: The biotransformation of xenobiotics is a homeostatic defensive response of the body against bioactive invaders. Xenobiotic metabolizing enzymes, important for the metabolism, elimination and detoxification of exogenous agents, are found in most tissues and organs and are distinguished into phase I and phase II enzymes, as well as phase III transporters. The cytochrome P450 superfamily of enzymes plays a major role in the biotransformation of most xenobiotics as well as in the metabolism of important endogenous substrates such as steroids and fatty acids. The activity and the potential toxicity of numerous drugs are strongly influenced by their biotransformation, mainly accomplished by the cytochrome P450 enzymes, one of the most versatile enzyme systems. OBJECTIVE: In this review, considering the importance of drug metabolising enzymes in health and disease, some of our previous research results are presented, which, combined with newer findings, may assist in the elucidation of xenobiotic metabolism and in the development of more efficient drugs. CONCLUSION: Study of drug metabolism is of major importance for the development of drugs and provides insight into the control of human health. This review is an effort towards this direction and may find useful applications in related medical interventions or help in the development of more efficient drugs.


Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Desenho de Drogas , Xenobióticos/metabolismo , Biotransformação/efeitos dos fármacos , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/metabolismo , Interações de Medicamentos , Humanos , Xenobióticos/química
4.
Bioorg Med Chem Lett ; 27(21): 4800-4804, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29017787

RESUMO

Novel amide derivatives of trolox, 3,5-di-tert-butyl-4-hydroxybenzoic acid, (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid and cinnamic acid with cysteamine and l-cysteine ethyl ester were synthesised. In four cases, the disulfide derivatives were also isolated and tested. All compounds were examined for antioxidant activity, expressed as their ability to inhibit lipid peroxidation and to scavenge free radicals. They were found to demonstrate up to 17-fold better activity than that of the parent antioxidant acids. They could reduce acute inflammation up to 87%. The most active antioxidant compounds were further tested for their in vivo hypolipidemic effect, which ranged from 47% to 73%, and for their ability to protect the liver against oxidative toxicity caused by high paracetamol dose. The disulfide derivatives of 3,5-di-tert-butyl-4-hydroxybenzoic acid and cinnamic acid had no antioxidant activity and presented equal or lower anti-inflammatory effect than their thiol analogues, indicating that their molecular characteristics may not permit biological barrier penetration.


Assuntos
Anti-Inflamatórios/química , Antioxidantes/química , Substâncias Protetoras/química , Acetaminofen/toxicidade , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/síntese química , Antioxidantes/farmacologia , Butanos/química , Carragenina/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cisteína/análogos & derivados , Cisteína/química , Edema/induzido quimicamente , Edema/prevenção & controle , Radicais Livres/química , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Parabenos/química , Substâncias Protetoras/síntese química , Substâncias Protetoras/farmacologia , Ratos
5.
Med Chem ; 13(5): 408-420, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28185540

RESUMO

BACKGROUND: Non-steroidal anti-inflammatory drugs are the oldest and most widely used medicines. However, their untoward effects, especially gastrointestinal toxicity, remain the main obstacle to their application. Because of their mechanism of action, cycloxygenase (COX) inhibition, in combination with the weekly acidic character of most of them, major protective mechanisms of the gastrointestinal system are suppressed and deregulated. OBJECTIVE: In this review, several compounds designed to retain anti-inflammatory activity, but devoid of gastrointestinal side effects, are presented. Thus, gastro-protective drugs, selective COX-2 inhibitors, nitric monoxide- and hydrogen sulphide-releasing agents, prodrugs, lipoxygenase (LOX) inhibitors and dual COX/LOX inhibitors are presented. Their mechanism of action, as well as their advantages and disadvantages are discussed. CONCLUSION: Efforts, aiming to the development of safe non-steroidal anti-inflammatory agents, are evolving, however there are still several problems concerning gastro-protection to be efficiently solved, thus, design of effective and safe agents for the treatment of inflammatory conditions still remains a major challenge.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Úlcera Péptica/prevenção & controle , Substâncias Protetoras/farmacologia , Animais , Química Farmacêutica , Colo/efeitos dos fármacos , Colo/patologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Mucosa Gástrica/fisiologia , Humanos , Sulfeto de Hidrogênio/metabolismo , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/patologia , Inibidores de Lipoxigenase/farmacologia , Óxido Nítrico/fisiologia , Doadores de Óxido Nítrico/farmacologia , Pró-Fármacos/farmacologia
6.
Molecules ; 22(2)2017 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-28218677

RESUMO

Stress can be defined as the homeostatic, nonspecific defensive response of the organism to challenges. It is expressed by morphological, biochemical, and functional changes. In this review, we present biological and oxidative stress, as well as their interrelation. In addition to the mediation in biologic stress (central nervous, immune, and hormonal systems) and oxidative stress, the effect of these phenomena on xenobiotic metabolism and drug response is also examined. It is concluded that stress decreases drug response, a result which seems to be mainly attributed to the induction of hepatic drug metabolizing enzymes. A number of mechanisms are presented. Structure-activity studies are also discussed. Vitamin E, as well as two synthetic novel compounds, seem to reduce both oxidative and biological stress and, consequently, influence drug response and metabolism.


Assuntos
Resistência a Medicamentos , Estresse Oxidativo , Estresse Fisiológico , Animais , Antioxidantes/metabolismo , Humanos , Especificidade de Órgãos , Oxidantes/metabolismo , Oxirredução , Esteroides/metabolismo , Esteroides/farmacologia , Relação Estrutura-Atividade , Xenobióticos/química , Xenobióticos/metabolismo , Xenobióticos/farmacologia
7.
Med Chem ; 13(3): 214-225, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27823562

RESUMO

OBJECTIVES: A series of esters and amides, incorporating an antioxidant residue, such as trolox or caffeic acid, and various moieties with different biological activities, were synthesised. The obtained compounds demonstrated considerable anti-inflammatory, radical scavenging and antioxidant action. Thus, they could reduce carrageenan-induced rat paw oedema by 31-60% at 150 µmol/kg and inhibit rat microsomal membrane lipid peroxidation with IC50 values as low as 1.4 µM, which is much lower than that of trolox. Most of them could also inhibit soybean lipoxygenase. The thiomorpholine derivatives decreased significantly all lipidemic indices of Triton-induced hyperlipidemia in rats. The most active, the caffeic acid derivative (6), decreases triglycerides, total cholesterol and low density lipoprotein, in the plasma of hyperlipidemic rats, by 70%, 67%, and 73%, respectively, at 150 µmol/kg (i.p.). CONCLUSION: The synthesised compounds, designed to exhibit two or more pharmacological actions, may be considered useful in the study of agents addressed to conditions involving inflammation and oxidative stress.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Cromanos/farmacologia , Edema/tratamento farmacológico , Hipolipemiantes/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antioxidantes/síntese química , Antioxidantes/química , Carragenina , Cromanos/síntese química , Cromanos/química , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Feminino , Hipolipemiantes/síntese química , Hipolipemiantes/química , Masculino , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 26(3): 910-913, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26750253

RESUMO

Novel amides of non steroidal anti-inflammatory drugs (NSAIDs), α-lipoic acid and indole-3-acetic acid with thiomorpholine were synthesised by a simple method and at high yields (60-92%). All the NSAID derivatives highly decreased lipidemic indices in the plasma of Triton treated hyperlipidemic rats. The most potent compound was the indomethacin derivative, which decreased total cholesterol, triglycerides and LDL cholesterol by 73%, 80% and 83%, respectively. They reduced acute inflammation equally or more than most parent acids. Hence, it could be concluded that amides of common NSAIDs with thiomorpholine acquire considerable hypolipidemic potency, while they preserve or augment their anti-inflammatory activity, thus addressing significant risk factors for atherogenesis.


Assuntos
Amidas/química , Anti-Inflamatórios não Esteroides/química , Hipolipemiantes/química , Morfolinas/química , Amidas/uso terapêutico , Animais , Colesterol/sangue , LDL-Colesterol/sangue , Edema/induzido quimicamente , Edema/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/patologia , Hipolipemiantes/uso terapêutico , Ratos , Triglicerídeos/sangue
9.
Bioorg Med Chem Lett ; 25(22): 5028-31, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26494261

RESUMO

Novel esters of non steroidal anti-inflammatory drugs, α-lipoic acid and indol-3-acetic acid with cinnamyl alcohol were synthesised by a straightforward method and at high yields (60-98%). They reduced acute inflammation more than the parent acids and are potent inhibitors of soybean lipoxygenase. Selected structures decreased plasma lipidemic indices in Triton-induced hyperlipidemia to rats. Therefore, the synthesised compounds may add to the current knowledge about agents acting against various inflammatory disorders.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Cinamatos/farmacologia , Inibidores de Lipoxigenase/farmacologia , Propanóis/química , Propionatos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/uso terapêutico , Carragenina , Cinamatos/síntese química , Cinamatos/uso terapêutico , Edema/induzido quimicamente , Edema/tratamento farmacológico , Ésteres , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/tratamento farmacológico , Ácidos Indolacéticos/química , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/uso terapêutico , Polietilenoglicóis , Propionatos/síntese química , Propionatos/uso terapêutico , Ratos , Soja , Ácido Tióctico/química
10.
Arch Pharm (Weinheim) ; 348(9): 629-34, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26191791

RESUMO

A number of thiomorpholine derivatives that are structurally similar to some substituted morpholines possessing antioxidant and hypocholesterolemic activity were synthesized. The new compounds incorporate an antioxidant moiety as the thiomorpholine N-substituent. The derivatives were found to inhibit the ferrous/ascorbate-induced lipid peroxidation of microsomal membrane lipids, with IC50 values as low as 7.5 µΜ. In addition, these compounds demonstrate hypocholesterolemic and hypolipidemic action. The most active compound (5) decreases the triglyceride, total cholesterol, and low-density lipoprotein levels in the plasma of Triton WR-1339-induced hyperlipidemic rats, by 80, 78, and 76%, respectively, at 56 mmol/kg (i.p.). They may also act as squalene synthase inhibitors. The above results indicate that the new molecules may be useful as leads for the design of novel compounds as potentially antiatherogenic factors.


Assuntos
Anticolesterolemiantes/síntese química , Anticolesterolemiantes/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacologia , Hiperlipidemias/tratamento farmacológico , Morfolinas/síntese química , Morfolinas/farmacologia , Animais , Biomarcadores/sangue , Colesterol/sangue , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Desenho de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Farnesil-Difosfato Farnesiltransferase/metabolismo , Hiperlipidemias/sangue , Hiperlipidemias/induzido quimicamente , Peroxidação de Lipídeos/efeitos dos fármacos , Lipoproteínas LDL/sangue , Estrutura Molecular , Polietilenoglicóis , Ratos , Relação Estrutura-Atividade , Triglicerídeos/sangue
11.
J Med Chem ; 52(22): 7315-8, 2009 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-19863055

RESUMO

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) or 3,5-di-tert-butyl-4-hydroxybenzoic acid (6). Compounds 5 and 6 inhibited lipid peroxidation, IC(50) 1.1 and 24 microM. 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%.


Assuntos
Antioxidantes/química , Antioxidantes/farmacologia , Desenho de Drogas , Estresse Fisiológico/efeitos dos fármacos , Amidas/química , Animais , Ansiolíticos/química , Ansiolíticos/farmacologia , Antioxidantes/síntese química , Antioxidantes/uso terapêutico , Benzoatos/química , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ácidos Carboxílicos/química , Cromanos/química , Dislipidemias/tratamento farmacológico , Dislipidemias/metabolismo , Esterificação , Peroxidação de Lipídeos/efeitos dos fármacos , Lorazepam/química , Lorazepam/farmacologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ácido gama-Aminobutírico/metabolismo
12.
J Med Chem ; 51(18): 5861-5, 2008 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-18754614

RESUMO

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 microM) as well as rat squalene synthase (IC50 for most between 1-10 microM). 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 micromol/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.


Assuntos
Antioxidantes/farmacologia , Inibidores Enzimáticos/farmacologia , Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Hipolipemiantes/farmacologia , Morfolinas/farmacologia , Animais , Antioxidantes/química , Colesterol/sangue , Inibidores Enzimáticos/química , Hipolipemiantes/química , Espectroscopia de Ressonância Magnética , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Morfolinas/química , Ratos , Triglicerídeos/sangue
13.
J Cardiovasc Pharmacol ; 51(6): 573-80, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18520953

RESUMO

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.


Assuntos
Antioxidantes/farmacologia , Aorta/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Colesterol/efeitos adversos , Doença da Artéria Coronariana/prevenção & controle , Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Morfolinas/farmacologia , Animais , Antioxidantes/efeitos adversos , Aorta/fisiopatologia , Compostos de Bifenilo/efeitos adversos , Dieta , Modelos Animais de Doenças , Lipídeos/sangue , Morfolinas/efeitos adversos , Coelhos
14.
J Pharmacol Exp Ther ; 323(3): 794-804, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17804677

RESUMO

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.


Assuntos
Aterosclerose/tratamento farmacológico , Compostos de Bifenilo/uso terapêutico , Colesterol na Dieta/efeitos adversos , Dieta Aterogênica , Inibidores Enzimáticos/uso terapêutico , Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Morfolinas/uso terapêutico , Animais , Aterosclerose/enzimologia , Aterosclerose/etiologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Compostos de Bifenilo/efeitos adversos , Compostos de Bifenilo/farmacologia , Colesterol na Dieta/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Masculino , Morfolinas/efeitos adversos , Morfolinas/farmacologia , Especificidade de Órgãos , Coelhos
15.
Bioorg Med Chem ; 15(2): 951-61, 2007 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-17126019

RESUMO

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.


Assuntos
Ibuprofeno/análogos & derivados , Ibuprofeno/síntese química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Nootrópicos/síntese química , Nootrópicos/farmacologia , Animais , Antioxidantes/síntese química , Antioxidantes/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/enzimologia , Compostos de Bifenilo , Barreira Hematoencefálica/metabolismo , Colesterol/sangue , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Adjuvante de Freund , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/patologia , Glutationa/metabolismo , Hiperlipidemias/sangue , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Ibuprofeno/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/farmacologia , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Fármacos Neuroprotetores/toxicidade , Nootrópicos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Picratos/antagonistas & inibidores , Picratos/toxicidade , Ratos , Baço/citologia , Baço/enzimologia , Triglicerídeos/sangue
17.
Eur J Pharmacol ; 535(1-3): 34-42, 2006 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-16545796

RESUMO

We investigated the effects of EP2306 and EP2302, two novel 2-biphenylmorpholine derivatives, on squalene synthase activity in rabbit and human liver microsomes, lipid biosynthesis, low-density lipoprotein (LDL) receptor expression and LDL protein uptake as well as apoB secretion in HepG2 cells. Both EP2306 and EP2302 inhibited squalene synthase activity dose-dependently. In rabbit liver microsomes, the IC50 values were 33 microM for EP2306 and 0.6 microM for EP2302 whereas in human liver microsomes, they were 63 microM for EP2306 and 1 microM for EP2302. Both EP2300 compounds inhibited cholesterol production by HepG2 cells dose dependently with IC50 values of 13.3 microM for EP2306 and 3 microM for EP2302. Furthermore, both EP2300 compounds and simvastatin significantly reduced triglyceride synthesis and apoB secretion and increased LDL receptor expression and LDL uptake in HepG2 cells. In summary, we have shown that EP2300 compounds are potent inhibitors of squalene synthase activity in rabbit and human liver microsomes and also they are effective inhibitors of cholesterol and triglyceride biosynthesis in HepG2 cells. These results suggest that EP2306 and EP2302 might prove to be useful for lipid-lowering and treatment of atherosclerosis in vivo.


Assuntos
Compostos de Bifenilo/farmacologia , Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Lipídeos/biossíntese , Morfolinas/farmacologia , Animais , Apolipoproteínas B/metabolismo , Transporte Biológico/efeitos dos fármacos , Linhagem Celular Tumoral , Colesterol/biossíntese , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Farnesil-Difosfato Farnesiltransferase/metabolismo , Humanos , Lipoproteínas LDL/farmacocinética , Microscopia de Fluorescência , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Coelhos , Receptores de LDL/metabolismo , Sinvastatina/farmacologia , Triglicerídeos/biossíntese
18.
Bioorg Med Chem Lett ; 16(4): 825-9, 2006 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-16309906

RESUMO

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.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Artrite/tratamento farmacológico , Inflamação/tratamento farmacológico , Ácidos Pipecólicos/farmacologia , Prolina/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Anticolesterolemiantes/síntese química , Anticolesterolemiantes/química , Anticolesterolemiantes/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Colesterol/sangue , Modelos Animais de Doenças , Desenho de Drogas , Avaliação Pré-Clínica de Medicamentos , Feminino , Ácidos Pipecólicos/síntese química , Ácidos Pipecólicos/química , Prolina/análogos & derivados , Prolina/síntese química , Ratos , Ratos Endogâmicos F344 , Relação Estrutura-Atividade , Triglicerídeos/sangue
20.
Arch Pharm (Weinheim) ; 338(7): 315-21, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15981300

RESUMO

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 alpha-tocopherol (alpha-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 alpha-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 alpha-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 alpha-toc, in combination with stress, further increases erythro mycin N-demethylation (CYP3A1) compared to stress control, while 4-nitrophenol hydroxylation (CYP2E1) is not affected significantly.


Assuntos
Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Estresse Fisiológico/fisiopatologia , alfa-Tocoferol/análogos & derivados , Administração Oral , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/patologia , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Hidrocarboneto de Aril Hidroxilases/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Temperatura Baixa , Corticosterona/sangue , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP3A , Feminino , Privação de Alimentos , Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Ratos Endogâmicos F344 , Timo/efeitos dos fármacos , Timo/patologia , Tocoferóis , alfa-Tocoferol/administração & dosagem , alfa-Tocoferol/farmacologia
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