RESUMO
This report summarizes the identification and synthesis of novel LpxC inhibitors aided by computational methods that leveraged numerous crystal structures. This effort led to the identification of oxazolidinone and isoxazoline inhibitors with potent in vitro activity against P. aeruginosa and other Gram-negative bacteria. Representative compound 13f demonstrated efficacy against P. aeruginosa in a mouse neutropenic thigh infection model. The antibacterial activity against K. pneumoniae could be potentiated by Gram-positive antibiotics rifampicin (RIF) and vancomycin (VAN) in both in vitro and in vivo models.
Assuntos
Amidoidrolases/antagonistas & inibidores , Isoxazóis/química , Isoxazóis/farmacologia , Oxazolidinonas/química , Oxazolidinonas/farmacologia , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação MolecularRESUMO
Synthetic modification of cyclosporin A at P3-P4 positions led to the discovery of NIM258, a next generation cyclophilin inhibitor with excellent anti-hepatitis C virus potency, with decreased transporter inhibition, and pharmacokinetics suitable for coadministration with other drugs. Herein is disclosed the evolution of the synthetic strategy to from the original medicinal chemistry route, designed for late diversification, to a convergent and robust development synthesis. The chiral centers in the P4 fragment were constructed by an asymmetric chelated Claisen rearrangement in the presence of quinidine as the chiral ligand. Identification of advanced crystalline intermediates enabled practical supply of key intermediates. Finally, macrocyclization was carried out at 10% weight concentration by a general and unconventional "slow release" concept.
Assuntos
Antivirais/química , Ciclosporina/química , Hepacivirus/fisiologia , Antivirais/síntese química , Antivirais/farmacologia , Ciclização , Ciclosporina/síntese química , Ciclosporina/farmacologia , Dipeptídeos/síntese química , Dipeptídeos/química , Desenho de Fármacos , Quinidina/química , Estereoisomerismo , Replicação Viral/efeitos dos fármacosRESUMO
Nonimmunosuppressive cyclophilin inhibitors have demonstrated efficacy for the treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A, and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction of the side chain hydrophobicity of the P4 residue preserves cyclophilin binding and antiviral potency while decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a less potent transporter inhibitor relative to previously described cyclosporins, retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic profile in rats and dogs. An X-ray structure of 33 bound to rat cyclophilin D is reported.
Assuntos
Antivirais/química , Antivirais/farmacologia , Ciclofilinas/antagonistas & inibidores , Ciclosporinas/farmacologia , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Técnicas de Química Sintética , Cristalografia por Raios X , Peptidil-Prolil Isomerase F , Ciclofilinas/química , Ciclofilinas/metabolismo , Ciclosporina/química , Ciclosporina/farmacologia , Ciclosporinas/química , Cães , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Humanos , Interações Hidrofóbicas e Hidrofílicas , Imunossupressores/química , Imunossupressores/farmacologia , Transportador 1 de Ânion Orgânico Específico do Fígado , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Ratos , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
Synthesis and SAR of 2-alkyloxazoles as class III phosphatidylinositol-4-kinase beta (PI4KIIIß) inhibitors is described. These compounds demonstrate that inhibition of PI4KIIIß leads to potent inhibition of HCV replication as observed in genotype (GT) 1a and 1b replicon and GT2a JFH1 virus assays in vitro.
Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Oxazóis/farmacologia , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Replicação Viral/efeitos dos fármacos , Antivirais/síntese química , Antivirais/química , Relação Dose-Resposta a Droga , Hepacivirus/enzimologia , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxazóis/síntese química , Oxazóis/química , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
The first multiple-site activation of alkynes with amine/halogen functionalities has been established. The reaction was performed by treating alkyne with N,N-dichlorobenzenesulfonamide at 80 degrees C in the presence of palladium acetate catalyst. A new mechanism was proposed which involves the novel formation of beta-halovinyl palladium and pi-allylpalladium species. Excellent regio- and stereoselectivities were achieved with the absolute structure determined by X-ray structural analysis.
