RESUMO
The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells and, as a consequence, is an attractive target for selective inhibition. This Letter describes the discovery of a new family of HCV NS5B non-nucleoside inhibitors, based on the bioisosterism between amide and phosphonamidate functions. As part of this program, SAR in this new series led to the identification of IDX17119, a potent non-nucleoside inhibitor, active on the genotypes 1b, 2a, 3a and 4a. The structure and binding domain of IDX17119 were confirmed by X-ray co-crystallization study.
Assuntos
Antivirais/farmacologia , Genótipo , Hepacivirus/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Sítio Alostérico , Antivirais/química , Antivirais/metabolismo , Cristalografia por Raios X , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismoRESUMO
We disclose here the synthesis of a series of macrocyclic HCV protease inhibitors, where the homoserine linked together the quinoline P2' motif and the macrocyclic moiety. These compounds exhibit potent inhibitory activity against HCV NS3/4A protease and replicon cell based assay. Their enzymatic and antiviral activities are modulated by substitutions on the quinoline P2' at position 8 by methyl and halogens and by small heterocycles at position 2. The in vitro structure activity relationship (SAR) studies and in vivo pharmacokinetic (PK) evaluations of selected compounds are described herein.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Homosserina/farmacologia , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Relação Dose-Resposta a Droga , Hepacivirus/enzimologia , Homosserina/síntese química , Homosserina/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Inibidores de Serina Proteinase/química , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismoRESUMO
Exploration of the P2 region by mimicking the proline motif found in BILN2061 resulted in the discovery of two series of potent HCV NS3/4A protease inhibitors. X-ray crystal structure of the ligand in contact with the NS3/4A protein and modulation of the quinoline heterocyclic region by structure based design and modeling allowed for the optimization of enzyme potency and cellular activity. This research led to the selection of clinical candidate IDX320 having good genotype coverage and pharmacokinetic properties in various species.
Assuntos
Descoberta de Drogas , Hepacivirus/efeitos dos fármacos , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Haplorrinos , Hepatócitos/enzimologia , Humanos , Concentração Inibidora 50 , Camundongos , Microssomos Hepáticos/enzimologia , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologia , Proteínas não Estruturais Virais/químicaRESUMO
Structural homology between thrombin inhibitors and the early tetrapeptide HCV protease inhibitor led to the bioisosteric replacement of the P2 proline by a 2,4-disubstituted azetidine within the macrocyclic ß-strand mimic. Molecular modeling guided the design of the series. This approach was validated by the excellent activity and selectivity in biochemical and cell based assays of this novel series and confirmed by the co-crystal structure of the inhibitor with the NS3/4A protein (PDB code: 4TYD).
Assuntos
Azetidinas/farmacologia , Desenho de Fármacos , Inibidores de Serina Proteinase/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Azetidinas/síntese química , Azetidinas/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Modelos Moleculares , Estrutura Molecular , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/química , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismoRESUMO
RNA viruses are the agents of numerous widespread and often severe diseases. Their unique RNA-dependent RNA polymerase (RDRP) is essential for replication and, thus, constitutes a valid target for the development of selective chemotherapeutic agents. In this regard, we have investigated sugar-modified ribonucleoside analogues as potential inhibitors of the RDRP. Title compounds retain 'natural' pyrimidine bases, but possess a beta-methyl substituent at the 2'-position of the D- or L-ribose moiety. Evaluation against a broad range of RNA viruses, either single-stranded positive (ssRNA+), single-stranded negative (ssRNA-) or double-stranded (dsRNA), revealed potent activities for D-2'-C-methyl-cytidine and -uridine against ssRNA+, and dsRNA viruses. None of the L-enantiomers were active. Moreover, the 5'-triphosphates of the active D-enantiomers were found to inhibit the bovine virus diarrhoea virus polymerase. Thus, the 2'-methyl branching of natural pyrimidine ribonucleosides transforms physiological molecules into potent, broad-spectrum antiviral agents that merit further development.
Assuntos
Antivirais/farmacologia , Nucleosídeos de Pirimidina/farmacologia , Vírus de RNA/efeitos dos fármacos , Vírus de RNA/fisiologia , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/química , Linhagem Celular , Cricetinae , Cães , Haplorrinos , Humanos , Estrutura Molecular , Nucleosídeos de Pirimidina/química , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Ribonucleoside analogs possessing a ß-methyl substituent at the 2'-position of the d-ribose moiety have been previously discovered to be potent and selective inhibitors of hepatitis C virus (HCV) replication, their triphosphates acting as alternative substrate inhibitors of the HCV RdRp NS5B. Results/methodology: In this article, the authors detail the synthesis, anti-HCV evaluation in cell-based replicon assays and structure-activity relationships of several phosphoramidate diester derivatives of 2'-C-methylguanosine (2'-MeG). CONCLUSION: The most promising compound, namely the O-[S-(hydroxyl)pivaloyl-2-thioethyl]{abbreviated as O-[(HO)tBuSATE)]} N-benzylamine phosphoramidate diester derivative (IDX184), was selected for further in vivo studies, and was the first clinical pronucleotide evaluated for the treatment of chronic hepatitis C up to Phase II trials.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Descoberta de Drogas , Guanosina Monofosfato/análogos & derivados , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Guanosina Monofosfato/síntese química , Guanosina Monofosfato/farmacologia , Humanos , Relação Estrutura-AtividadeRESUMO
The potent anti-HIV-1 activities of L-737,126 (2) and PAS sulfones prompted us to design and test against HIV-1 in acutely infected MT-4 cells a number of novel 1- and 3-benzenesulfonylindoles. Indoles belonging to the 1-benzenesulfonyl series were found poorly or totally inactive. On the contrary, some of the 3-benzenesulfonyl derivatives turned out to be as potent as 2, being endowed with potencies in the low nanomolar concentration range. In particular, (2-methylphenyl)sulfonyl (72) and (3-methylphenyl)sulfonyl (73) derivatives showed EC(50) values of 1 nM. Introduction of two methyl groups at positions 3 and 5 of the phenyl ring of 2 furnished derivatives (80 and 83) which showed very potent and selective anti-HIV-1 activity not only against the wt strain, but also against mutants carrying NNRTI-resistant mutations at positions 103 and 181 of the reverse transcriptase gene.
Assuntos
Fármacos Anti-HIV/síntese química , Farmacorresistência Viral/genética , HIV-1/efeitos dos fármacos , Indóis/síntese química , Inibidores da Transcriptase Reversa/síntese química , Sulfonas/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Linhagem Celular , HIV-1/genética , Humanos , Indóis/química , Indóis/farmacologia , Mutação , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacologiaRESUMO
A novel series of 1-[2-(diarylmethoxy)ethyl]-2-methyl-5-nitroimidazole (DAMNI) analogues were synthesized and tested in cell-based assays and in enzyme assays against HIV-1 recombinant reverse transcriptase (RT). Preparation of the new derivatives was performed by reacting the appropriate benzhydrols or the corresponding bromides with 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole or the 3-hydroxypropyl homologue. Several compounds showed anti-HIV-1 activity in the submicromolar range. Structure-activity relationship studies suggested that meta substitution at one phenyl ring of the diarylmethane moiety strongly influences the antiviral activity. The 3,5-disubstitution at the same phenyl ring led to less potent derivatives. Molecular modeling and docking studies within the RT non-nucleoside binding site confirmed that DAMNIs, similar to other NNRTIs such as TNK-651 and delavirdine (BHAP U90152), assume a butterfly-like conformation that appears to be halfway between that of classical NNRTIs, such as nevirapine, HEPT, TBZ, TIBO, and DABOs, and the conformation of BHAPs. In particular, the diphenylmethane moiety mimics the wings whereas the 1-(2-methyl-5-nitroimidazolyl)ethane portion resembles the BHAP 5-methanesulfonamidoindole-2-carbonylpiperazine portion.
Assuntos
Transcriptase Reversa do HIV/química , Imidazóis/síntese química , Inibidores da Transcriptase Reversa/síntese química , Animais , Linhagem Celular , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Imidazóis/química , Imidazóis/farmacologia , Modelos Moleculares , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Replicação ViralRESUMO
beta-L-2'-Deoxycytidine (beta-L-dC) is a potent, selective and specific anti-hepatitis B virus (HBV) agent. To improve its oral bioavailability, several derivatives involving sugar or base acylation, as well N4-derivatization with an N,N-(dimethylamino)methylene function, were synthesized. The physicochemical characteristics (including chemical stabilities, solubilities and distribution coefficient values) and pharmacokinetics of these compounds were determined and compared with those of the parent drug, beta-L-dC.
Assuntos
Antivirais/síntese química , Desoxicitidina/análogos & derivados , Desoxicitidina/síntese química , Vírus da Hepatite B/efeitos dos fármacos , Pró-Fármacos/síntese química , Acilação , Administração Oral , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Disponibilidade Biológica , Desoxicitidina/farmacocinética , Desoxicitidina/farmacologia , Haplorrinos , Vírus da Hepatite B/metabolismo , Testes de Sensibilidade Microbiana , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , SolubilidadeRESUMO
A new class of acyclic nucleoside phosphonates PMAMG, PMAMA, PMAMC, and PMAMT (compounds 1, 2, 3 and 4) have been synthesized and tested in vitro against a wide variety of viruses, fungi and bacteria. PMAMG (1) was synthesized by the alkylation reaction of acetylguanine with the phosphonate side-chain, diisopropyl [[2-(bromomethyl)aziridin-1-yl]]methylphosphonate (9), followed by deesterification reaction in the presence of TMSBr. In similar way, PMAMA, PMAMC, and PMAMT were prepared.
Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Aziridinas/síntese química , Aziridinas/farmacologia , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Organofosfonatos/síntese química , Organofosfonatos/farmacologia , Alquilação , Animais , Antibacterianos , Antivirais/síntese química , Antivirais/farmacologia , Linhagem Celular , Esterificação , Guanina/análogos & derivados , Humanos , Testes de Sensibilidade Microbiana , Shigella/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Streptococcaceae/classificação , Streptococcaceae/efeitos dos fármacos , Relação Estrutura-Atividade , Vírus/efeitos dos fármacos , Leveduras/efeitos dos fármacosRESUMO
Three 7-fluoro-7-deaza-2-aminopurine nucleoside derivatives were synthesized and evaluated as potential inhibitors of RNA virus replication, including hepatitis C virus (HCV).
Assuntos
Antivirais/síntese química , Nucleosídeos de Purina/síntese química , Antivirais/química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Nucleosídeos de Purina/química , Nucleosídeos de Purina/farmacologiaRESUMO
9-Deazaguanosine and the alpha and beta anomers of its 2'-C-methyl counter part, have been synthesized and evaluated against a broad range of RNA viruses, including hepatitis C virus.
Assuntos
Antivirais/síntese química , Guanosina/análogos & derivados , Antivirais/química , Antivirais/farmacologia , Flavivirus/efeitos dos fármacos , Guanosina/síntese química , Guanosina/química , Guanosina/farmacologia , Hepacivirus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
A series of novel 4-fluoro-1H-pyrazole-3-carboxamide nucleoside analogues were synthesized and evaluated as potential inhibitors of RNA virus replication, including hepatitis C virus (HCV).
Assuntos
Antivirais/síntese química , Ribavirina/análogos & derivados , Antivirais/química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacosRESUMO
The first example of a nucleoside analogue bearing a 5'-deoxy-beta-D-allo-septanose as the sugar moiety was synthesized and evaluated as a potential inhibitor of several virus replication.