RESUMO
In this report we describe the synthesis and evaluation of diverse 4-arylproline analogs as HCV NS3 protease inhibitors. Introduction of this novel P2 moiety opened up new SAR and, in combination with a synthetic approach providing a versatile handle, allowed for efficient exploitation of this novel series of NS3 protease inhibitors. Multiple structural modifications of the aryl group at the 4-proline, guided by structural analysis, led to the identification of analogs which were very potent in both enzymatic and cell based assays. The impact of this systematic SAR on different drug properties is reported.
Assuntos
Antivirais/síntese química , Hepacivirus/enzimologia , Prolina/análogos & derivados , Inibidores de Proteases/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/farmacocinética , Sítios de Ligação , Desenho de Fármacos , Meia-Vida , Hepacivirus/fisiologia , Simulação de Acoplamento Molecular , Prolina/síntese química , Prolina/farmacocinética , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Estrutura Terciária de Proteína , Ratos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
We describe here the design, synthesis and biological evaluation of antiviral compounds acting against human rhinovirus (HRV). A series of aminothiazoles demonstrated pan-activity against the HRV genotypes screened and productive structure-activity relationships. A comprehensive investigational library was designed and performed allowing the identification of potent compounds with lower molecular weight and improved ADME profile. 31d-1, 31d-2, 31f showed good exposures in CD-1 mice. The mechanism of action was discovered to be a host target: the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIß). The identification of the pan-HRV active compound 31f combined with a structurally distinct literature compound T-00127-HEV1 allowed the assessment of target related tolerability of inhibiting this kinase for a short period of time in order to prevent HRV replication.
Assuntos
Antivirais/farmacologia , Desenho de Fármacos , Rhinovirus/efeitos dos fármacos , Tiazóis/farmacologia , Antivirais/síntese química , Antivirais/química , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/químicaRESUMO
Amino-quinazoline BRaf kinase inhibitor 2 was identified from a library screen as a modest inhibitor of the unfolded protein response (UPR) regulating potential anticancer target IRE1α. A combination of crystallographic and conformational considerations were used to guide structure-based attenuation of BRaf activity and optimization of IRE1α potency. Quinazoline 6-position modifications were found to provide up to 100-fold improvement in IRE1α cellular potency but were ineffective at reducing BRaf activity. A salt bridge contact with Glu651 in IRE1α was then targeted to build in selectivity over BRaf which instead possesses a histidine in this position (His539). Torsional angle analysis revealed that the quinazoline hinge binder core was ill-suited to accommodate the required conformation to effectively reach Glu651, prompting a change to the thienopyrimidine hinge binder. Resulting analogues such as 25 demonstrated good IRE1α cellular potency and imparted more than 1000-fold decrease in BRaf activity.
RESUMO
The inadequate efficacy and tolerability of current therapies for the infectious liver disease caused by the hepatitis C virus have warranted significant efforts in the development of new therapeutics. We have previously reported competitive peptide inhibitors of the NS3 serine protease based on the N-terminal cleavage products of peptide substrates. A detailed study of the interactions of these substrate-based inhibitors with the different subsites of the serine protease active site led to the discovery of novel residues that increased the affinity of the inhibitors. In this paper, we report the combination of the best binding residues in a tetrapeptide series that resulted in extremely potent inhibitors that bind exquisitely well to this enzyme. A substantial increase in potency was obtained with the simultaneous introduction of a 7-methoxy-2-phenyl-4-quinolinoxy moiety at the gamma-position of the P2 proline and a tert-leucine as a P3 residue. The increase in potency allowed for the further truncation and led to the identification of tripeptide inhibitors. Structure activity relationship studies on this inhibitor series led to the identification of carbamate-containing tripeptides that are able to inhibit replication of subgenomic HCV RNA in cell culture with potencies below 1 microM. This inhibitor series has the potential of becoming antiviral agents for the treatment of HCV infections.
Assuntos
Antivirais/síntese química , Oligopeptídeos/síntese química , Quinolinas/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Antivirais/farmacologia , Sítios de Ligação , Carbamatos/síntese química , Carbamatos/química , Carbamatos/farmacologia , Proteínas de Transporte/química , Células Cultivadas , Cristalografia por Raios X , Hepacivirus/genética , Humanos , Ligação de Hidrogênio , Peptídeos e Proteínas de Sinalização Intracelular , Modelos Moleculares , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Ligação Proteica , Quinolinas/química , Quinolinas/farmacologia , RNA Viral/biossíntese , Estereoisomerismo , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/química , Proteínas Virais/químicaRESUMO
From the discovery of competitive hexapeptide inhibitors, potent and selective HCV NS3 protease macrocyclic inhibitors have been identified. Structure-activity relationship studies were performed focusing on optimizing the N-terminal carbamate and the aromatic substituent on the (4R)-hydroxyproline moiety. Inhibitors meeting the potency criteria in the cell-based assay and with improved oral bioavailability in rats were identified. BILN 2061 was selected as the best compound, the first NS3 protease inhibitor reported with antiviral activity in man.
Assuntos
Antivirais/síntese química , Carbamatos/síntese química , Hepacivirus/enzimologia , Compostos Heterocíclicos/síntese química , Inibidores de Proteases/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Animais , Antivirais/química , Antivirais/farmacologia , Disponibilidade Biológica , Carbamatos/química , Carbamatos/farmacologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Injeções Intravenosas , Prolina/química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
The synthesis of BILN 2061, an NS3 protease inhibitor with proven antiviral effect in humans, was accomplished in a convergent manner from four building blocks. The procedure described here was suitable for the preparation of multigram quantities of BILN 2061 for preclinical pharmacological evaluation.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Carbamatos/síntese química , Carbamatos/farmacologia , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Carbamatos/química , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Humanos , Compostos Macrocíclicos/química , Estrutura Molecular , Inibidores de Proteases/química , Quinolinas/química , Tiazóis/química , Proteínas não Estruturais Virais/metabolismoRESUMO
C-Terminal carboxylic acid containing inhibitors of the NS3 protease are reported. A novel series of linear tripeptide inhibitors that are very potent and selective against the NS3 protease are described. A substantial contribution to the potency of these linear inhibitors arises from the introduction of a C8 substituent on the B-ring of the quinoline moiety found on the P2 of these inhibitors. The introduction of a C8 methyl group results not only in a modest increase in the cell-based potency of these inhibitors but more importantly in a much better pharmacokinetic profile in rats as well. Exploration of C8-substitutions led to the identification of the bromo derivative as the best group at this position, resulting in a significant increase in the cell-based potency of this class of inhibitors. Structure-activity studies on the C8-bromo derivatives ultimately led to the discovery of clinical candidate 29 (BI 201335), a very potent and selective inhibitor of genotype1 NS3 protease with a promising PK profile in rats.