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1.
Eur J Med Chem ; 264: 115991, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38118393

RESUMO

Hepatitis C infection is caused by the bloodborne pathogen hepatitis C virus (HCV) and can lead to serious liver diseases and, ultimately, death if the treatment is ineffective. This work reports the synthesis and preclinical evaluation of 7 novel 9-O/N/S pyrimidine nucleosides, including compound 12, the triphosphate of known compound 7b. The nucleosides are 9-deaza modifications of adenosine and guanosine with ß-2'-C-methyl substituent on the ribose. Within this series of compounds, a 9-deaza furopyrimidine analog of adenosine, compound 7b, showed high anti-HCV activity in vitro, good stability, low toxicity, and low genotoxicity when administrated in low doses, and an adequate pharmacokinetics profile. An improved synthesis of compound 7b compared to a previous study is also reported. Compound 12 was synthesized as a control to verify phosphorylation of 7b occurred in vivo.


Assuntos
Hepatite C , Nucleosídeos de Pirimidina , Humanos , Nucleosídeos/farmacologia , Hepacivirus , RNA Polimerase Dependente de RNA , Nucleosídeos de Pirimidina/farmacologia , Hepatite C/tratamento farmacológico , Adenosina , Antivirais
2.
Artigo em Inglês | MEDLINE | ID: mdl-36354089

RESUMO

As a part of our ongoing discovery efforts exploring azasugar as agents for treating various unmet medical needs, we prepared analogs of azasugar as potential anti-hepatitis C virus (HCV) agents. Herein we describe the synthesis of novel 2'ß-C-Me 9-deazanucleoside azasugar analogs.


Assuntos
Hepatite C , Nucleosídeos , Humanos , Hepacivirus , Hepatite C/tratamento farmacológico , Antivirais
3.
J Med Chem ; 64(17): 12453-12468, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34436898

RESUMO

Hereditary angioedema (HAE) is a rare and potentially life-threatening disease that affects an estimated 1 in 50 000 individuals worldwide. Until recently, prophylactic HAE treatment options were limited to injectables, a burdensome administration route that has driven the need for an oral treatment. A substantial body of evidence has shown that potent and selective plasma kallikrein inhibitors that block the generation of bradykinin represent a promising approach for the treatment of HAE. Berotralstat (BCX7353, discovered by BioCryst Pharmaceuticals using a structure-guided drug design strategy) is a synthetic plasma kallikrein inhibitor that is potent and highly selective over other structurally related serine proteases. This once-daily, small-molecule drug is the first orally bioavailable prophylactic treatment for HAE attacks, having successfully completed a Phase III clinical trial (meeting its primary end point) and recently receiving the U.S. Food and Drug Administration's approval for the prophylactic treatment of HAE attacks in patients 12 years and older.


Assuntos
Angioedemas Hereditários/tratamento farmacológico , Calicreínas/antagonistas & inibidores , Pirazóis/química , Pirazóis/farmacologia , Administração Oral , Domínio Catalítico , Desenho de Fármacos , Humanos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Conformação Proteica , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade
4.
Bioorg Med Chem ; 17(11): 3934-58, 2009 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-19409795

RESUMO

Factor VIIa (FVIIa), a serine protease enzyme, coupled with tissue factor (TF) plays an important role in a number of thrombosis-related disorders. Inhibition of TF x FVIIa occurs early in the coagulation cascade and might provide some safety advantages over other related enzymes. We report here a novel series of substituted biphenyl derivatives that are highly potent and selective TF x FVIIa inhibitors. Parallel synthesis coupled with structure-based drug design allowed us to explore the S2 pocket of the enzyme active site. A number of compounds with IC(50) value of <10 nM were synthesized. The X-ray crystal structures of some of these compounds complexed with TF x FVIIa were determined and results were applied to design the next round of inhibitors. All the potent inhibitors were tested for inhibition against a panel of related enzymes and selectivity of 17,600 over thrombin, 450 over trypsin, 685 over FXa, and 76 over plasmin was achieved. Two groups, vinyl 36b and 2-furan 36ab, were identified as the optimum binding substituents on the phenyl ring in the S2 pocket. Compounds with these two substituents are the most potent compounds in this series with good selectivity over related serine proteases. These compounds will be further explored for structure-activity relationship.


Assuntos
Anticoagulantes/química , Anticoagulantes/farmacologia , Compostos de Bifenilo , Coagulação Sanguínea/efeitos dos fármacos , Desenho de Fármacos , Fator VIIa/antagonistas & inibidores , Sítios de Ligação , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Domínio Catalítico , Cristalografia por Raios X , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
5.
Acta Crystallogr D Biol Crystallogr ; 63(Pt 6): 689-97, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17505107

RESUMO

Factor VIIa (FVIIa) is a trypsin-like serine protease in the coagulation cascade. Its complex with tissue factor (TF) triggers the extrinsic pathway of the coagulation cascade, generating a blood clot. Research programs at several centers now recognize the important roles played by TF and FVIIa in both the thrombotic and inflammatory processes associated with cardiovascular diseases. Therefore, inhibition of the TF-FVIIa complex is seen as a promising target that is key to the development of clinical candidates for various cardiovascular applications. The crystal structure of the TF-FVIIa enzyme complex has been analyzed in order to design and synthesize small-molecule inhibitors. Using structure-based drug design (SBDD), a new series of inhibitors have been discovered that demonstrate high potency against the TF-FVIIa complex while maintaining substantial selectivity versus other closely related serine proteases such as trypsin, thrombin, factor Xa and plasmin.


Assuntos
Fator VIIa/antagonistas & inibidores , Fator VIIa/química , Piridinas/química , Piridinas/farmacologia , Tromboplastina/química , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Técnicas In Vitro , Modelos Moleculares , Estrutura Molecular , Complexos Multiproteicos/química
6.
Bioorg Med Chem ; 15(5): 2106-19, 2007 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-17218104

RESUMO

Benzoic acid and pyridine derivatives inhibit recombinant trans-sialidase from Trypanosoma cruzi with I50 values between 0.4 and 1mM. The best compounds, 4-acetylamino-3-hydroxymethylbenzoic acid and 5-acetylamino-6-aminopyridine-2-carboxylic acid, provide new leads to inhibitors not containing the synthetically complex sialic acid structure. The weak inhibition by such compounds contrasts with their much stronger inhibition of neuraminidase from Influenza virus.


Assuntos
Ácido Benzoico/farmacologia , Inibidores Enzimáticos/farmacologia , Glicoproteínas/antagonistas & inibidores , Neuraminidase/antagonistas & inibidores , Piridinas/farmacologia , Trypanosoma cruzi/enzimologia , Animais , Ácido Benzoico/química , Inibidores Enzimáticos/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Piridinas/química , Espectrometria de Massas por Ionização por Electrospray
7.
Artigo em Inglês | MEDLINE | ID: mdl-16541957

RESUMO

The introduction of versatile functional groups, allyl and ester, at the C-1 position of the acyclic chain in acyclic adenine nucleosides was achieved for the first time directly by alkylation of adenine and N6-potected adenine. Thus, the C-1'-substituted N9-adenine acyclic nucleoside, adenine-9-yl-pent-4-enoic acid ethyl ester (11), was prepared by direct alkylation of adenine with 2-bromopent-4-enoic acid ethyl ester (6), while the corresponding N7-regioisomer, 2-[6-(dimethylaminomethyleneamino)-purin-7-yl]-pent-4-enoic acid ethyl ester (10), was obtained in one step by the coupling of N, N-dimethyl-N'- (9H-purin-6-yl)-formamidine (9) with 2-bromopent-4-enoic acid ethyl ester (6). The functional groups, ester and allyl, were converted to the desired hydroxymethyl and hydroxyethyl groups, and subsequently to phosphonomethyl derivatives and corresponding pyrophosphorylphosphonates.


Assuntos
Adenina/análogos & derivados , Adenina/síntese química , Carbono/química , Nucleosídeos/síntese química , Adenina/química , Alquilação , Antivirais/síntese química , Antivirais/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Nucleosídeos/química
8.
Bioorg Med Chem ; 13(12): 4071-7, 2005 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-15911320

RESUMO

Cyclopentane derivatives, designated as BCX-1812, BCX-1827, BCX-1898, and BCX-1923, were tested in parallel with oseltamivir carboxylate and zanamivir for the in vivo activity in mice infected with A/Turkey/Mas/76 X A/Beijing/32/92 (H6N2) influenza virus. The compounds were tested orally and intranasally at different dose levels. BCX-1812, BCX-1827, and BCX-1923 showed more than 50% protection at 1mg/kg/day dose level on oral treatment. The intranasal treatment was 100% effective even at 0.01 mg/kg/day for all four compounds. On comparison with oseltamivir carboxylate and zanamivir, these four cyclopentane derivatives have shown equal or better efficacies. The synthesis of two new compounds, BCX-1898 and BCX-1923, is also described.


Assuntos
Antivirais/síntese química , Ciclopentanos/administração & dosagem , Ciclopentanos/síntese química , Orthomyxoviridae/efeitos dos fármacos , Acetamidas/farmacologia , Ácidos Carbocíclicos , Administração Intranasal , Administração Oral , Animais , Antivirais/administração & dosagem , Antivirais/farmacologia , Ciclopentanos/farmacologia , Relação Dose-Resposta a Droga , Guanidinas , Camundongos , Infecções por Orthomyxoviridae/tratamento farmacológico , Oseltamivir , Piranos , Ácidos Siálicos/farmacologia , Relação Estrutura-Atividade , Taxa de Sobrevida , Resultado do Tratamento , Zanamivir
9.
Bioorg Med Chem ; 13(7): 2665-78, 2005 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-15755666

RESUMO

Based upon the activity and X-ray crystallographic studies of tri-substituted benzene derivatives containing carboxylic acid, acetamido and guanidine groups, we investigated the effect of the fourth substituent to fulfill the fourth pocket of neuraminidase enzyme. The groups selected as fourth substituents were hydroxymethyl, hydroxyethyl, oxime and amino. These tetra-substituted benzene derivatives were synthesized and evaluated for neuraminidase inhibitory activity. All these compounds were found to have poorer IC(50) values than the tri-substituted compounds. Further, benzene ring was replaced by pyridine ring and di, tri and tetra-substituted pyridine derivatives were synthesized. The activity of the pyridine derivatives was comparable to benzene derivatives. The fourth substituent seems to disturb the binding of the other three substituents, so the activity is reduced as compared to tri-substituted benzene and pyridine derivatives.


Assuntos
Benzoatos/síntese química , Benzoatos/farmacologia , Neuraminidase/antagonistas & inibidores , Orthomyxoviridae/enzimologia , Piridinas/síntese química , Piridinas/farmacologia , Benzoatos/química , Cristalografia por Raios X , Modelos Moleculares , Conformação Molecular , Piridinas/química , Relação Estrutura-Atividade
10.
Nucleosides Nucleotides Nucleic Acids ; 24(10-12): 1543-68, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16438034

RESUMO

Acyclic N9 adenine nucleosides substituted at C-1' position were prepared by the Mitsunobu reaction of 1-tert-butyldimethylsilyl-4-pivaloylbutan-1,2,4-triol (5) with adenine. Pivaloyl hydroxyl was modified to the phosphonomethoxy derivatives, and the tert-butyldimethylsilyl hydroxyl was converted to methoxy, azido, amino, fluoro, and c-hydroxyethyl and was eliminated to give vinyl. The resulting phosphonic acids were converted to prodrugs also.


Assuntos
Adenina/síntese química , Antivirais/síntese química , Hepacivirus/crescimento & desenvolvimento , Organofosfonatos/síntese química , Pró-Fármacos/síntese química , Replicação Viral/efeitos dos fármacos , Adenina/análogos & derivados , Adenina/farmacologia , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Humanos , Organofosfonatos/farmacologia , Pró-Fármacos/farmacologia
11.
Nucleosides Nucleotides Nucleic Acids ; 24(10-12): 1569-85, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16438035

RESUMO

Various C-1'-substituted acyclic N9 adenine nucleosides were prepared from 9-[(1-hydroxymethyl)(3-monomethoxytrityloxy)propyl]-N6-monomethoxytrityladenine. The hydroxymethyl was modified to the phosphonomethoxy derivative, and the 3-monomethoxytrityloxy was converted to hydroxyl, methoxy, azido, and amino. Other substituents, such as ethyl and ea-hydroxyethyl were also prepared. The resulting phosphonomethoxy derivatives were converted to prodrugs.


Assuntos
Adenina/síntese química , Antivirais/síntese química , Hepacivirus/crescimento & desenvolvimento , Organofosfonatos/síntese química , Pró-Fármacos/síntese química , Replicação Viral/efeitos dos fármacos , Adenina/análogos & derivados , Adenina/farmacologia , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Humanos , Organofosfonatos/farmacologia , Pró-Fármacos/farmacologia
12.
Nucleosides Nucleotides Nucleic Acids ; 24(10-12): 1587-95, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16438036

RESUMO

The appropriately protected C-1'-hydroxyethyl-3-hydroxypropyl-N9-adenine nucleoside was prepared from 1-pivaloyloxy-5-tert-butyldiphenylsilyloxy-3-pentanol and adenine through the Mitsunobu reaction. One of the terminal hydroxyls was converted to the phosphonomethoxy derivative and the prodrug.


Assuntos
Adenina/síntese química , Antivirais/síntese química , Hepacivirus/crescimento & desenvolvimento , Organofosfonatos/síntese química , Pró-Fármacos/síntese química , Replicação Viral/efeitos dos fármacos , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Organofosfonatos/farmacologia , Pró-Fármacos/farmacologia
13.
Nucleosides Nucleotides Nucleic Acids ; 24(10-12): 1597-611, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16438037

RESUMO

A number of N6-substituted 9-[3-(phosphonomethoxy)propyl]adenine derivatives having hydroxymethyl at C-1' position were prepared from the appropriate 6-chloroadenine derivative. The syntheses of the corresponding prodrugs of these compounds are also reported. These compounds showed poor activity against HCV in replicon assay.


Assuntos
Adenina/síntese química , Antivirais/síntese química , Hepacivirus/crescimento & desenvolvimento , Organofosfonatos/síntese química , Pró-Fármacos/síntese química , Replicação Viral/efeitos dos fármacos , Adenina/análogos & derivados , Adenina/farmacologia , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Humanos , Organofosfonatos/farmacologia , Pró-Fármacos/farmacologia
14.
J Med Chem ; 47(8): 1919-29, 2004 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-15055992

RESUMO

In further studies aimed toward identifying effective and safe inhibitors of influenza neuraminidases, we synthesized a series of multisubstituted cyclopentane amide derivatives. Amides prepared were 14 examples of N-substituted alkyl or aralkyl types from primary amines, 13 examples of the N,N-disubstituted alkyl, aralkyl, or substituted-alkyl type from secondary amines, and 12 examples from cycloaliphatic or substituted cycloaliphatic secondary amines. These compounds bearing two chiral centers, at position-1 in the ring and position-1' in the side chain attached at position 3, were tested for their ability to inhibit A and B forms of influenza neuraminidase. The 1-ethylpropylamide, diethylamide, dipropylamide, and 4-morpholinylamide showed very good inhibitory activity (IC(50) = 0.015-0.080 microM) vs the neuraminidase A form, but modest activity (IC(50) = 3.0-9.2 microM) vs the neuraminidase B form. Since the parent amides bear two chiral centers (C-1 and C-1'), three of the better inhibitors were tested at higher levels of diastereomeric purity. The diastereomers corresponding to the active forms of the 1-(ethyl)propylamide, the diethylamide, and the dipropylamide (all of the same configuration at the C-1' chiral center), and the diastereomer of the diethylamide representing the active form at both C-1' and C-1 were isolated or synthesized from precursors that were isolated as diastereomers. These diastereomers showed some improvement in neuraminidase inhibition over the parent diastereomeric mixtures. 1-Carboxy-1-hydroxy derivatives of the best active compounds, the diethylamide and the dipropylamide, were also prepared. These compounds were not as active as the compounds without the 1-hydroxy group. In an in vivo study, the C-1' active isomer of the diethylamide from the 1-carboxy series was tested in influenza-infected mice by oral and intranasal administration and found to be very effective only intranasally in preventing weight loss at doses as low as 0.1 (mg/kg)/day.


Assuntos
Amidas/síntese química , Antivirais/síntese química , Ciclopentanos/síntese química , Neuraminidase/antagonistas & inibidores , Administração Intranasal , Amidas/química , Amidas/farmacologia , Animais , Antivirais/química , Antivirais/farmacologia , Cristalografia por Raios X , Ciclopentanos/química , Ciclopentanos/farmacologia , Vírus da Influenza A/enzimologia , Camundongos , Modelos Moleculares , Neuraminidase/química , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/virologia , Estereoisomerismo , Relação Estrutura-Atividade
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