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1.
J Med Chem ; 53(8): 3075-85, 2010 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-20302300

RESUMO

HCV infection affects more than 170 million people worldwide and many of those patients will reach the end stage complications of the disease which include hepatocarcinoma and liver failure. The success rate for treatment of patients infected with genotype-1 is about 40%. Therefore, novel treatments are needed to combat the infection. The HCV NS3 protease inhibitor Boceprevir (1) was reported by our research group and efforts continue for the discovery of more potent compounds with improved pharmacokinetic profiles. A new series of HCV NS3 protease inhibitors having a cyclic sulfone P3-cap have been discovered. Compounds 43 and 44 showed K(i)* values in the single-digit nM range and their cellular potency was improved by 10-fold compared to 1. The pharmacokinetic profiles of 43 and 44 in rats and monkeys were also improved to achieve higher plasma levels after oral administration.


Assuntos
Hepacivirus/enzimologia , Oligopeptídeos/síntese química , Inibidores de Serina Proteinase/síntese química , Sulfonas/síntese química , Administração Oral , Animais , Cristalografia por Raios X , Haplorrinos , Modelos Moleculares , Oligopeptídeos/farmacocinética , Oligopeptídeos/farmacologia , Ratos , Inibidores de Serina Proteinase/farmacocinética , Inibidores de Serina Proteinase/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonas/farmacocinética , Sulfonas/farmacologia
2.
J Synchrotron Radiat ; 15(Pt 3): 204-7, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18421139

RESUMO

The structures of both native and S139A holo-HCV NS3/4A protease domain were solved to high resolution. Subsequently, structures were determined for a series of ketoamide inhibitors in complex with the protease. The changes in the inhibitor potency were correlated with changes in the buried surface area upon binding the inhibitor to the active site. The largest contributions to the binding energy arise from the hydrophobic interactions of the P1 and P2 groups as they bind to the S1 and S2 pockets. This correlation of the changes in potency with increased buried surface area contributed directly to the design of a potent tripeptide inhibitor of the HCV NS3/4A protease, which is currently in clinical trials.


Assuntos
Hepacivirus/enzimologia , Prolina/análogos & derivados , Inibidores de Proteases/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Modelos Moleculares , Estrutura Molecular , Prolina/química
3.
J Med Chem ; 50(10): 2310-8, 2007 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-17444623

RESUMO

The structures of both the native holo-HCV NS3/4A protease domain and the protease domain with a serine 139 to alanine (S139A) mutation were solved to high resolution. Subsequently, structures were determined for a series of ketoamide inhibitors in complex with the protease. The changes in the inhibitor potency were correlated with changes in the buried surface area upon binding the inhibitor to the active site. The largest contribution to the binding energy arises from the hydrophobic interactions of the P1 and P2 groups as they bind to the S1 and S2 pockets [the numbering of the subsites is as defined in Berger, A.; Schechter, I. Philos. Trans. R. Soc. London, Ser. B 1970, 257, 249-264]. This correlation of the changes in potency with increased buried surface area contributed directly to the design of a potent tripeptide inhibitor of the HCV NS3/4A protease that is currently in clinical trials.


Assuntos
Antivirais/síntese química , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/química , Hepacivirus/enzimologia , Prolina/análogos & derivados , Inibidores de Serina Proteinase/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/química , Antivirais/química , Sítios de Ligação , Cristalografia por Raios X , Peptídeos e Proteínas de Sinalização Intracelular , Modelos Moleculares , Prolina/síntese química , Prolina/química , Conformação Proteica , Estereoisomerismo , Relação Estrutura-Atividade
4.
J Med Chem ; 49(9): 2750-7, 2006 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-16640336

RESUMO

Introduction of various modified prolines at P(2) and optimization of the P(1) side chain led to the discovery of SCH6 (24, Table 2), a potent ketoamide inhibitor of the HCV NS3 serine protease. In addition to excellent enzyme potency (K(i)*= 3.8 nM), 24 was also found to be a potent inhibitor of HCV subgenomic RNA replication with IC(50) and IC(90) of 40 and 100 nM, respectively. Recently, antiviral activity of 24 was demonstrated with inhibition of the full-length genotype 2a HCV genome. In addition, 24 was found to restore the responsiveness of the interferon regulatory factor 3 (IRF-3) in cells containing HCV RNA replicons.


Assuntos
Amidas/química , Amidas/farmacologia , Genoma Viral/genética , Hepacivirus/efeitos dos fármacos , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Serina Endopeptidases/metabolismo , Animais , Haplorrinos , Hepacivirus/enzimologia , Hepacivirus/genética , Modelos Moleculares , Estrutura Molecular , RNA Viral/genética , Ratos , Serina Endopeptidases/química , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologia , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo
6.
Bioorg Med Chem Lett ; 12(13): 1739-42, 2002 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-12067550

RESUMO

The four 2,2,5-regioisomer counterparts of SCH 51048 were synthesized and evaluated. As with the parent series, only the two cis isomers possessed any in vitro activity, and only the activity of the isomer with the R-configuration at the tetrahydrofuran 2-carbon was significant. The activity data suggests that oxygen at only one of the two possible ring positions benzylic to the difluorobenzene participates usefully in active site binding.


Assuntos
Antifúngicos/síntese química , Furanos/síntese química , Triazóis/química , Antifúngicos/química , Antifúngicos/farmacologia , Benzeno/química , Sítios de Ligação , Furanos/química , Furanos/farmacologia , Técnicas In Vitro , Testes de Sensibilidade Microbiana , Oxigênio/química , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/farmacologia
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