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1.
Int J Mol Sci ; 19(11)2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30380747

RESUMO

Opuntia ficus indica (OFI) is grown abundantly in arid areas and its fruits are regarded as an important food and nutrient source owing to the presence of flavonoids, minerals, and proteins. The previous report that OFI exerts phytoestrogenic activity makes it plausible for OFI-containing supplements to be used as alternative estrogen replacement therapy. In the case of polypharmacy with the consumption of OFI-containing botanicals in post- or peri-menopausal women, it is critical to determine the potential drug-OFI interaction due to the modulation of drug metabolism. In the present study, the modulating effects on the hepatic drug metabolizing enzymes (DMEs) by OFI and its flavonoid constituents (kaempferol, quercetin, isorhamnetin, and their glycosidic forms) were investigated using the liver microsomal fractions prepared from ovariectomized (OVX) rats, human liver microsomes, and human hepatocarcinoma cell line (HepG2). As a result, the oral administration of extracts of OFI (OFIE) in OVX rats induced hepatic CYP2B1, CYP3A1, and UGT2B1. OFIE, hydrolyzed (hdl) OFIE, and several flavonols induced the transcriptional activities of both CYP2B6 and CYP3A4 genes in HepG2 cells. Finally, OFIE did not inhibit activities of cytochrome P450 (CYPs) or uridine diphosphate (UDP)-glucuronosyltransferases (UGTs), whereas hdl OFIE or flavonol treatment inhibited CYP1A2 and CYP3A1/3A4 in rat and human liver microsomes. Our data demonstrate that OFIE may induce or inhibit certain types of DMEs and indicate that drug-OFI interaction may occur when the substrate or inhibitor drugs of specific CYPs or UGTs are taken concomitantly with OFI-containing products.


Assuntos
Indutores das Enzimas do Citocromo P-450/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Flavonoides/farmacologia , Glucuronosiltransferase , Opuntia/química , Extratos Vegetais/farmacologia , Animais , Indutores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/química , Feminino , Flavonoides/química , Glucuronosiltransferase/antagonistas & inibidores , Glucuronosiltransferase/metabolismo , Células Hep G2 , Humanos , Microssomos Hepáticos/enzimologia , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley
2.
Molecules ; 23(7)2018 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-29949932

RESUMO

Sakuranetin (SKN), found in cherry trees and rice, is a flavanone with various pharmacological activities. It is biosynthesized from naringenin in rice or cherry trees, and the metabolism of SKN has been studied in non-human species. The present study aimed to investigate the metabolic pathways of SKN in human liver microsomes and identify the phase I and phase II metabolites, as well as evaluate the potential for drug⁻herb interactions through the modulation of drug metabolizing enzymes (DMEs). HPLC-DAD and HPLC-electrospray mass spectrometry were used to study the metabolic stability and identify the metabolites from human liver microsomes incubated with SKN. The potential of SKN to inhibit the DMEs was evaluated by monitoring the formation of a DME-specific product. The cytochrome P450 2B6 and 3A4-inductive effects were studied using promoter reporter assays in human hepatocarcinoma cells. The major pathways for SKN metabolism include B-ring hydroxylation, 5-O-demethylation, and conjugation with glutathione or glucuronic acid. The phase I metabolites were identified as naringenin and eriodictyol. SKN was found to be a UDP-glucuronosyltransferases (UGT) 1A9 inhibitor, whereas it induced transactivation of the human pregnane X receptor-mediated cytochrome P450 (CYP) 3A4 gene.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Flavonoides/metabolismo , Glucuronosiltransferase/metabolismo , Fígado/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/genética , Células Hep G2 , Humanos , Fígado/efeitos dos fármacos , Desintoxicação Metabólica Fase I , Desintoxicação Metabólica Fase II , Metaboloma , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , NADP/metabolismo , Receptor de Pregnano X , Regiões Promotoras Genéticas/genética , Receptores de Esteroides/metabolismo , Ativação Transcricional/genética , Uridina Difosfato Ácido Glucurônico/metabolismo
3.
Bioorg Med Chem Lett ; 28(11): 2080-2083, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29709253

RESUMO

In order to replace thiourea group with the more drug-like moiety for 1,3-dibenzylthioureas having TRPV1 antagonist activity, we introduced a set of functional groups between the two aromatic rings based on bioisosteric replacement. The synthesized bioisosteres of 1,3-dibenzylthioureas were tested for their antagonist activities on TRPV1 by 45Ca2+-influx assay using neonatal rat cultured spinal sensory neurons. Among the tested 14 kinds of bioisosters, 2-methylacrylamide group was the best candidate to replace thiourea group. Compound 7c, 2-methylacrylamide analog of ATC-120, showed as potent as ATC-120 in its antagonist activity. In addition, 2-methylacrylamide analog 7e having vinyl moiety showed the most potent activity with 0.022 µM of IC50 value, indicating that thiourea group of 1,3-dibenzylthioureas could be replaced to 2-methylacrylamide without loss of their potencies.


Assuntos
Acrilamidas/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Tioureia/farmacologia , Acrilamidas/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tioureia/análogos & derivados , Tioureia/química
4.
Arch Pharm Res ; 38(12): 2131-6, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26219510

RESUMO

The first asymmetric synthesis of (R,R)-clemastine (1) has been accomplished by the coupling of (R)-tertiary alcohol 2 and (R)-chloroethylpyrrolidine 3 via O-alkylation. (R)-Tertiary alcohol 2 was synthesized by stereoselective alkylation of chiral α-benzyloxy ketone with Grignard reagent via chelation-controlled 1,4-asymmetric induction. In the reaction, chiral benzyl group acts as a chiral auxiliary as well as a protecting group. (R)-Chloroethylpyrrolidine 3 was prepared by asymmetric transformation starting with L-homoserine lactone, in which racemization-minimized N-allylation and ring-closing metathesis were involved as key steps.


Assuntos
Química Farmacêutica/métodos , Clemastina/síntese química , Antagonistas dos Receptores Histamínicos H1/síntese química , Receptores Histamínicos H1/química , Estereoisomerismo
5.
Bioorg Med Chem Lett ; 24(5): 1403-6, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24507928

RESUMO

A novel biological activity of psoralidin as an agonist for both estrogen receptor (ER)α and ERß agonist has been demonstrated in our study. Psoralidin has been characterized as a full ER agonist, which activates the classical ER-signaling pathway in both ER-positive human breast and endometrial cell lines as well as non-human cultured cells transiently expressing either ERα or ERß. The estrogenic activity was determined using the relative expression levels of either reporter or the endogenous genes dependent on the agonist-bound ER to the estrogen response element (ERE). Psoralidin at 10 µM was able to induce the maximum reporter gene expression corresponding to that of E2-treated cells and such activation of the ERE-reporter gene by psoralidin was completely abolished by the cotreatment of a pure ER antagonist, implying that the biological activities of psoralidin are mediated by ER. Psoralidin was also able to induce the endogenous estrogen-responsive gene, pS2, in human breast cancer cells MCF-7. It was observed that activation of the classical ER-signaling pathway by psoralidin is mediated via induction of ER conformation by psoralidin and direct binding of the psoralidin-ER complex to the EREs present in the promoter region of estrogen-responsive genes, as shown by chromatin immunoprecipitation assay results. Finally, molecular docking of psoralidin to the ligand binding pocket of the ERα showed that psoralidin is able to mimic the binding interactions of E2, and thus, it could act as an ER agonist in the cellular environment.


Assuntos
Benzofuranos/química , Cumarínicos/química , Psoralea/química , Receptores de Estrogênio/metabolismo , Benzofuranos/isolamento & purificação , Benzofuranos/farmacologia , Sítios de Ligação , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cumarínicos/isolamento & purificação , Cumarínicos/farmacologia , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/agonistas , Receptor beta de Estrogênio/metabolismo , Feminino , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Psoralea/metabolismo , Receptores de Estrogênio/agonistas , Transdução de Sinais/efeitos dos fármacos
6.
Arch Pharm Res ; 36(9): 1096-103, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23613312

RESUMO

We have designed the cyclopropane analog of stilbene as subtype-selective ligands for estrogen receptor based on the bioisosterism that cyclopropane could act as alkene bioisoster. Three cyclopropane analogs were prepared efficiently starting from 4-benzyloxybenzaldehyde, and evaluated for their binding to estrogen receptors ERα and ERß. These cyclopropane analogs were also found to be full agonists in estrogen receptor-mediated gene transcription assay. Compared to the stilbene analogs such as tamoxifen and raloxifene, the three cyclopropane analogs showed lower binding affinity for estrogen receptor, but higher subtype selectivity for ERα. The structure-activity relationship revealed from this study might provide clues for improving subtype selectivity for ERα.


Assuntos
Ciclopropanos/farmacologia , Desenho de Fármacos , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Cloridrato de Raloxifeno/análogos & derivados , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Estilbenos/farmacologia , Animais , Ligação Competitiva , Linhagem Celular , Chlorocebus aethiops , Ciclopropanos/síntese química , Ciclopropanos/química , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/agonistas , Receptor beta de Estrogênio/antagonistas & inibidores , Receptor beta de Estrogênio/genética , Terapia de Reposição de Estrogênios/efeitos adversos , Estrogênios/síntese química , Estrogênios/química , Estrogênios/farmacologia , Genes Reporter/efeitos dos fármacos , Humanos , Ligantes , Estrutura Molecular , Cloridrato de Raloxifeno/química , Cloridrato de Raloxifeno/farmacologia , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Elementos de Resposta/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/síntese química , Moduladores Seletivos de Receptor Estrogênico/química , Estereoisomerismo , Estilbenos/síntese química , Estilbenos/química , Relação Estrutura-Atividade
7.
Chem Asian J ; 8(2): 400-9, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23208797

RESUMO

A series of heterocycle-linked constrained phenylbenzyl amides were found to be TRPV1 antagonists with promising in vivo profiles. In particular, one of the analogues containing a furan linker exhibited excellent TRPV1 antagonistic activity and in vivo analgesic efficacy. In addition, the binding modes of dibenzyl thiourea, benzylphenethyl amide, and furan-linked phenylbenzyl amide were examined by using the flexible docking study within the rTRPV1 homology model.


Assuntos
Amidas/química , Compostos Heterocíclicos/química , Canais de Cátion TRPV/antagonistas & inibidores , Amidas/farmacocinética , Amidas/uso terapêutico , Analgésicos/síntese química , Analgésicos/farmacocinética , Analgésicos/uso terapêutico , Animais , Sítios de Ligação , Furanos/química , Meia-Vida , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Masculino , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Tioureia/química
8.
Arch Pharm Res ; 35(2): 321-6, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22370786

RESUMO

A series of chain branched 1,3-dibenzylthiourea derivatives were designed, synthesized, and evaluated for their antagonist activity against TRPV1. The synthesized chain branched 1,3-dibenzylthioureas 9a-g were tested for their antagonist activities against TRPV1 by (45)Ca(2+)-influx assay using neonatal rat cultured spinal sensory neurons. Fluorinated ethyl-branched analog 9g showed the most potent antagonist activity with an IC(50) value of 0.41 µM, but all of the chain branched analogs were less potent than the parent compounds MK-056 and SC-0030, indicating that chain branching on the benzylic position of B-ring is detrimental to potency. Optimized receptor binding seems to be interfered by chain branching, and resulted in decrease in potency.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Tioureia/análogos & derivados , Tioureia/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/química , Química Farmacêutica/métodos , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais , Relação Estrutura-Atividade , Tioureia/química
9.
Arch Pharm Res ; 33(2): 197-202, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20195818

RESUMO

Based on fluorine switch approach, a series of 3'-fluoropenciclovir analogues with different purine and pyrimidine bases were designed and synthesized. Direct reduction of beta-fluoroester to the corresponding 3-fluoroalcohol provided an easy and new entry pathway towards the synthesis of 3'-fluoropenciclovir analogues. The synthesized 3'-fluoropenciclovir analogues were evaluated for their antiviral activities against the poliovirus, HSV-1, HSV-2 and HIV.


Assuntos
Aciclovir/análogos & derivados , Antivirais/síntese química , Desenho de Fármacos , Aciclovir/síntese química , Aciclovir/química , Aciclovir/farmacologia , Antivirais/química , Antivirais/farmacologia , HIV-1/efeitos dos fármacos , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Poliovirus/efeitos dos fármacos
10.
Bioorg Med Chem ; 18(1): 111-6, 2010 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19931463

RESUMO

In searching for opportunities to exploit the benefits of silicon in TRPV1 research, we tried to investigate the pharmacological effects of sila-substitution (C/Si exchange) of tert-butyl group in the MK-056 series. Compound 13a, with a 4-positioned trimethylsilanyl group on the B ring in place of tert-butyl group, exhibited the most potent antagonist activity with IC(50) values of 0.15 microM, which is almost equipotent with that of MK-056. This is the first example that tert-butyl group on MK-056 series can be replaced to the other substituent without loss of activity.


Assuntos
Feniltioureia/análogos & derivados , Silício/química , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo , Animais , Cálcio/metabolismo , Células Cultivadas , Estrutura Molecular , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Feniltioureia/química , Feniltioureia/farmacologia , Ratos , Ratos Sprague-Dawley
11.
Bioorg Med Chem ; 17(24): 8149-60, 2009 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-19897373

RESUMO

Structural optimization of multiple H-bonding region and structure-activity relationship of diarylalkyl amides/thioamides as novel TRPV1 antagonists are described. In particular, we identified amide 34o and thioamides 35o and 35r, of which antagonistic activities were highly enhanced by an incorporation of cyano or vinyl-substituent to the multiple H-bonding region. They exhibited potent (45)Ca(2+) uptake inhibitions in rat DRG neuron with IC(50)s of 25, 32 and 28 nM, respectively.


Assuntos
Amidas/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Canais de Cátion TRPV/antagonistas & inibidores , Amidas/metabolismo , Animais , Sítios de Ligação , Cálcio/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Concentração Inibidora 50 , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
12.
Bioorg Med Chem Lett ; 19(11): 3088-92, 2009 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-19394216

RESUMO

A series of phenylisothioureas were synthesized as inhibitors of NO production in lipopolysaccharide-activated macrophages. We investigated the effect of lipophilic moiety and N- or S-substituents of the phenylisothioureas on the activity. Inhibitory activities of carbazole-linked phenylisothioureas were superior to the corresponding simple phenylisothiourea derivatives. Among these compounds, 12b having N-ethyl and S-isopropyl groups on phenylisothiourea moiety was the most potent in the inhibition of NO production. They inhibited NO production through the suppression of the LPS-induced translocation of p65 subunit of NF-kappaB and the followed suppression of the iNOS protein and mRNA expression.


Assuntos
Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico/metabolismo , Tioureia/química , Macrófagos/efeitos dos fármacos , NF-kappa B/metabolismo , Tioureia/síntese química , Tioureia/farmacologia
13.
Bioorg Med Chem ; 17(10): 3557-67, 2009 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-19398205

RESUMO

We have developed a new class of diarylalkyl amides as novel TRPV1 antagonists. They exhibited potent (45)Ca(2+) uptake inhibitions in rat DRG neuron. In particular, the amide 59 was identified as a potent antagonist with IC(50) of 57 nM. The synthesis and structure-activity relationship of the diarylalkyl amides are also described.


Assuntos
Amidas/síntese química , Sulfonamidas/síntese química , Canais de Cátion TRPV/antagonistas & inibidores , Tetra-Hidronaftalenos/síntese química , Amidas/química , Amidas/farmacologia , Animais , Cálcio/metabolismo , Células Cultivadas , Desenho de Fármacos , Concentração Inibidora 50 , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Canais de Cátion TRPV/metabolismo , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacologia
14.
Arch Pharm Res ; 32(1): 59-63, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19183877

RESUMO

Some C-benzylated flavonoids based on gericudranin A were synthesized and evaluated their cytotoxic activities for the elucidation of structure-activity relationship. 2,4,6-Trihydroxyacetophenone was converted to target molecules in 6 approximately 7 steps via sequential protection, aldol condensation, cyclization, regioselective C-benzylation, and deprotection. The cellular growth inhibition of the synthetic C-benzylated flavonoids was investigated against sixteen human cancer cell lines. Among these compounds, 5b showed the most potent cytotoxicities against several cell lines, especially as potent as adriamycin against SNB19 cell lines with an IC(50) value of 0.7 microM.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Quercetina/análogos & derivados , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Quercetina/síntese química , Quercetina/farmacologia , Relação Estrutura-Atividade
15.
Bioorg Med Chem Lett ; 19(3): 937-40, 2009 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-19110419

RESUMO

The overproduction of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) causes neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Four lignans, (+)-eudesmin (1), (+)-magnolin (2), (+)-yangambin (3) and a new structure named as epimagnolin B (4) were isolated from Magnolia fargesii (Magnoliaceae) as the inhibitors of NO production in LPS-activated microglia. The most potent compound 4 inhibited the production of NO and PGE(2) and the expression of respective enzyme iNOS and COX-2 through the suppression of I-kappaB-alpha degradation and nuclear translocation of p65 subunit of NF-kappaB.


Assuntos
Anti-Inflamatórios/farmacologia , Lignanas/química , Magnolia/metabolismo , Extratos Vegetais/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Ciclo-Oxigenase 2/metabolismo , Humanos , Proteínas I-kappa B/metabolismo , Lignina/química , Espectroscopia de Ressonância Magnética , Inibidor de NF-kappaB alfa , Neurônios/metabolismo , Óxido Nítrico/química , Óxido Nítrico/metabolismo , Fator de Transcrição RelA/metabolismo
16.
Bioorg Med Chem Lett ; 18(5): 1612-6, 2008 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-18255292

RESUMO

On the basis of potent and selective A(3) adenosine receptor (AR) antagonist, 2-chloro-N(6)-(3-iodobenzyl)-4'-thioadenosine-5'-N,N-dimethyluronamide, structure-activity relationships were studied for a series of 5'-N,N-dialkyluronamide derivatives, synthesized from D-gulonic gamma-lactone. From this study, it was revealed that removal of the hydrogen bond-donating ability of the 5'-uronamide was essential for the pure A(3)AR antagonism. 5'-N,N-Dimethyluronamide derivatives exhibited higher binding affinity than larger 5'-N,N-dialkyl or 5'-N,N-cycloalkylamide derivatives, indicating that steric factors are crucial in binding to the human A(3)AR. A N(6)-(3-bromobenzyl) derivative 6c (K(i)=9.32 nM) exhibited the highest binding affinity at the human A(3)AR with very low binding affinities to other AR subtypes.


Assuntos
Antagonistas do Receptor A3 de Adenosina , Amidas/química , Amidas/farmacologia , Ácidos Urônicos/química , Ácidos Urônicos/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
17.
Bioorg Med Chem Lett ; 18(6): 2179-82, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18276135
18.
Int J Pharm ; 341(1-2): 50-7, 2007 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-17517483

RESUMO

Ketoprofen-polyethylene glycol (PEG) conjugates (KPEG) were prepared and their potential as a prolonged release system was investigated. Three KPEG conjugates were synthesized from ketoprofen and methoxy PEG with three different molecular weights by esterification in the presence of DCC. The KPEG conjugates were characterized by FT-IR and (1)H NMR spectroscopy. The rate of hydrolysis profile showed a specific acid-base catalysis pattern with a minimum at pH 4-5. The pharmacokinetic study after the intravenous and intramuscular administration of KPEG750 showed that the plasma levels of KP increased slowly and reached a maximum concentration at later time. The AUC of KPEG750 was higher than that after administering an equivalent dose of ketoprofen except 40mg/kg dose of intramuscular administration. The tail-flick experiment and paw edema test after intramuscular administration showed that KPEG750 had extended analgesic and anti-inflammatory effects compared with ketoprofen. These results suggest that KPEG could be a promising NSAID prodrug with an extended pharmacological effect owing to delayed-release of parent drug.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Portadores de Fármacos , Cetoprofeno/farmacocinética , Polietilenoglicóis/química , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/sangue , Anti-Inflamatórios não Esteroides/síntese química , Carragenina , Química Farmacêutica , Preparações de Ação Retardada , Dicicloexilcarbodi-Imida/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Composição de Medicamentos , Concentração de Íons de Hidrogênio , Hidrólise , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Injeções Intramusculares , Injeções Intravenosas , Cetoprofeno/administração & dosagem , Cetoprofeno/análogos & derivados , Cetoprofeno/sangue , Cetoprofeno/síntese química , Espectroscopia de Ressonância Magnética , Masculino , Peso Molecular , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Pró-Fármacos/administração & dosagem , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Ratos , Ratos Sprague-Dawley , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier
19.
Arch Pharm Res ; 30(12): 1521-5, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18254238

RESUMO

Hydroxyclemastine was targeted as a versatile analogue of clemastine with H1 receptor antagonist activity. Stereoselective synthesis of (-)-hydroxyclemastine was performed in which the key step was chelation-controlled diastereoselective 1,2-addition of Grignard reagent to alpha-alkoxyketone.


Assuntos
Clemastina/síntese química , Antagonistas dos Receptores Histamínicos H1/síntese química , Estereoisomerismo
20.
Chem Pharm Bull (Tokyo) ; 54(3): 377-9, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16508196

RESUMO

Analogues of yakuchinones were synthesized as inhibitors of nitric oxide production in lipopolysaccharide-activated macrophage cell line, RAW 264.7 cells. We prepared stronger inhibitors than the original natural molecules, yakuchinones A and B reported from Alpinia oxyphylla. From the limited structural activity relation study of analogues, we concluded that the optimal length of linker between two aryl groups and the presence of enone moiety in the linker were identified as essential for the activity. The IC50 value of the most potent structure was 0.92 microM. The active analogues suppressed the expression of inducible nitric oxide synthase protein and mRNA.


Assuntos
Diarileptanoides/síntese química , Diarileptanoides/farmacologia , Inibidores Enzimáticos/farmacologia , Óxido Nítrico Sintase Tipo II/biossíntese , Alpinia/química , Animais , Western Blotting , Linhagem Celular , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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