RESUMO
Herein we describe the discovery of IDX21437 35b, a novel RPd-aminoacid-based phosphoramidate prodrug of 2'-α-chloro-2'-ß-C-methyluridine monophosphate. Its corresponding triphosphate 6 is a potent inhibitor of the HCV NS5B RNA-dependent RNA polymerase (RdRp). Despite showing very weak activity in the in vitro Huh-7 cell based HCV replicon assay, 35b demonstrated high levels of active triphosphate 6 in mouse liver and human hepatocytes. A biochemical study revealed that the metabolism of 35b was mainly attributed to carboxyesterase 1 (CES1), an enzyme which is underexpressed in HCV Huh-7-derived replicon cells. Furthermore, due to its metabolic activation, 35b was efficiently processed in liver cells compared to other cell types, including human cardiomyocytes. The selected RP diastereoisomeric configuration of 35b was assigned by X-ray structural determination. 35b is currently in Phase II clinical trials for the treatment of HCV infection.
Assuntos
Antivirais/farmacologia , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Uridina Monofosfato/análogos & derivados , Uridina/farmacologia , Animais , Antivirais/síntese química , Antivirais/química , RNA Polimerases Dirigidas por DNA/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Hepacivirus/enzimologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/virologia , Humanos , Fígado/efeitos dos fármacos , Fígado/virologia , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Uridina/síntese química , Uridina/química , Uridina Monofosfato/síntese química , Uridina Monofosfato/química , Uridina Monofosfato/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , 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
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
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).