RESUMO
[15 N]-Cholamine is an isotope tag for metabolomics research, because it possesses 2 important properties: an NMR active isotope and a permanent charge for MS sensitivity. Here, we present a scalable synthesis of [15 N]-cholamine.
Assuntos
Isótopos de Nitrogênio/química , Compostos de Trimetil Amônio/química , Brometos/química , Ácidos Carboxílicos/química , Espectroscopia de Ressonância Magnética/métodos , Espectrometria de Massas/métodosRESUMO
The discovery of a novel series of pyrrolopyrazines as JAK inhibitors with comparable enzyme and cellular activity to tofacitinib is described. The series was identified using a scaffold hopping approach aided by structure based drug design using principles of intramolecular hydrogen bonding for conformational restriction and targeting specific pockets for modulating kinase activity.
Assuntos
Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/química , Pirróis/química , Desenho de Fármacos , Humanos , Janus Quinase 3/metabolismo , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Fosforilação , Piperidinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Relação Estrutura-AtividadeRESUMO
The introduction of N-substituted pyrazoles in a new series of CCR5 antagonists was shown to substantially increase antiviral activity.
Assuntos
Fármacos Anti-HIV/química , Antagonistas dos Receptores CCR5 , Pirazóis/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Humanos , Pirazóis/síntese química , Pirazóis/farmacologia , Receptores CCR5/metabolismo , Relação Estrutura-AtividadeRESUMO
Replacement of a secondary amide with a piperidine or azetidine moiety in a series of CCR5 antagonists led to the discovery of compounds with increased intrinsic permeability. This effort led to the identification of a potent CCR5 antagonist which exhibited an improved in vivo pharmacokinetic profile.
Assuntos
Amidas/química , Compostos Aza/farmacologia , Antagonistas dos Receptores CCR5 , Compostos Aza/química , Compostos Aza/farmacocinética , Relação Estrutura-AtividadeRESUMO
The bicyclic 5-amino-3-azabicyclo[3.3.0]octanes were shown to be effective replacements for the 3-amino-8-azabicyclo[3.2.1]octane found in the CCR5 antagonist maraviroc.
Assuntos
Fármacos Anti-HIV/química , Compostos Azabicíclicos/química , Antagonistas dos Receptores CCR5 , Cicloexanos/química , Inibidores da Fusão de HIV/química , Triazóis/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Linhagem Celular Tumoral , Cicloexanos/síntese química , Cicloexanos/farmacologia , Inibidores da Fusão de HIV/síntese química , Inibidores da Fusão de HIV/farmacologia , Humanos , Maraviroc , Modelos Químicos , Receptores CCR5/metabolismo , Triazóis/síntese química , Triazóis/farmacologiaRESUMO
Replacement of a secondary amide with an N-acyl or N-sulfonyl gem-disubstituted azacyle in a series of CCR5 antagonists led to the identification of compounds with excellent in vitro HIV antiviral activity and increased intrinsic membrane permeability.
Assuntos
Amidas/química , Fármacos Anti-HIV/química , Compostos Aza/química , Antagonistas dos Receptores CCR5 , Inibidores da Fusão de HIV/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Compostos Aza/síntese química , Compostos Aza/farmacologia , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular/efeitos dos fármacos , Inibidores da Fusão de HIV/síntese química , Inibidores da Fusão de HIV/farmacologia , Humanos , Receptores CCR5/metabolismoRESUMO
The bicyclic 5-amino-3-azabicyclo[3.3.0]octanes were shown to be effective replacements for the conformationally restricted 4-aminopiperidine ring found in several series of CCR5 antagonists.
Assuntos
Antagonistas dos Receptores CCR5 , Avaliação Pré-Clínica de Medicamentos , Piperidinas/química , Modelos MolecularesRESUMO
Starting with a high-throughput screening lead, a novel series of CCR5 antagonists was developed utilizing an information-based approach. Improvement of pharmacokinetic properties for the series was pursued by SAR exploration of the lead template. The synthesis, SAR and biological profiles of the series are described.
Assuntos
Fármacos Anti-HIV/química , Benzamidas/química , Antagonistas dos Receptores CCR5 , Inibidores da Fusão de HIV/química , Pirróis/química , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Benzamidas/síntese química , Benzamidas/farmacologia , Inibidores da Fusão de HIV/síntese química , Inibidores da Fusão de HIV/farmacocinética , Humanos , Microssomos Hepáticos/metabolismo , Pirróis/síntese química , Pirróis/farmacocinética , Ratos , Receptores CCR5/metabolismo , Relação Estrutura-AtividadeRESUMO
In the past few years, there have been many advances in the efforts to cure patients with hepatitis C virus (HCV). The ultimate goal of these efforts is to develop a combination therapy consisting of only direct-antiviral agents (DAAs). In this paper, we discuss our efforts that led to the identification of a bicyclic template with potent activity against the NS5B polymerase, a critical enzyme on the life cycle of HCV. In continuation of our exploration to improve the stilbene series, the 3,5,6,8-tetrasubstituted quinoline core was identified as replacement of the stilbene moiety. 6-Methoxy-2(1H)-pyridone was identified among several heterocyclic headgroups to have the best potency. Solubility of the template was improved by replacing a planar aryl linker with a saturated pyrrolidine. Profiling of the most promising compounds led to the identification of quinoline 41 (RG7109), which was selected for advancement to clinical development.
Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Quinolinas/farmacologia , Sulfonamidas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/farmacocinética , Cães , Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Hepacivirus/enzimologia , Humanos , Modelos Moleculares , Quinolinas/química , Quinolinas/farmacocinética , Ratos , Sulfonamidas/química , Sulfonamidas/farmacocinéticaRESUMO
This review will focus on the discovery and clinical development of small molecule antagonists of CCR5 for the treatment of HIV-1/AIDS, as well as for the potential treatment of inflammatory diseases. In particular, we will focus on the specific medicinal chemistry problems that were faced during the discovery of the molecules. We will also describe limited data from clinical development phases focusing on specific issues that arose during the clinical trials. Finally, we will touch on the mechanism of action of CCR5 antagonists.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antagonistas dos Receptores CCR5 , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/química , HIV-1/efeitos dos fármacos , Humanos , Peso MolecularRESUMO
We describe in this paper the synthesis of 1,2-di-O-acetyl-5-azido-3,5-dideoxy-alpha,beta-L-arabinofuranose, a carbohydrate donor that was used for the synthesis of 1-(5'-amino-3',5'-dideoxy-alpha-L-arabinofuranosyl)uracil, the nucleoside found in dihydropacidamycin D. The carbohydrate donor was also used for the synthesis of a set of new nucleosides that were introduced in new dihydropacidamycins. These compounds were tested for biological activity, and the results showed that uracil is the only base recognized by MraY.
Assuntos
Antibacterianos/síntese química , Anti-Infecciosos/síntese química , Carboidratos/química , Peptídeos , Nucleosídeos de Pirimidina/síntese química , Transferases (Outros Grupos de Fosfato Substituídos)/metabolismo , Uracila/química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Configuração de Carboidratos , Relação Estrutura-AtividadeRESUMO
Dihydropacidamycins having an antibacterial spectrum modified from that of the natural product pacidamycins and mureidomycins have been synthesized. Synthetic dihydropacidamycins with noteworthy antibacterial activity against wild-type and resistant Escherichia coli have been identified (MIC=4-8 microg/mL). Some dihydropacidamycins are shown to have activity against multi-resistant clinical strains of Mycobacterium tuberculosis. Compounds of this class are inhibitors of the cell wall biosynthetic enzyme, MraY.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Peptídeos/síntese química , Peptídeos/farmacologia , Nucleosídeos de Pirimidina/síntese química , Nucleosídeos de Pirimidina/farmacologia , Bactérias Aeróbias Gram-Negativas/efeitos dos fármacos , Bactérias Aeróbias Gram-Negativas/crescimento & desenvolvimento , HumanosRESUMO
The discovery of a series of quinazolinone-based fungal efflux pump inhibitors by high-throughput screening for potentiation of fluconazole in C. albicans is described. Attempts to improve the aqueous solubility of screening hits led to the discovery of an analog with greatly improved physical properties and activity against clinically-relevant Candida spp.
Assuntos
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Antifúngicos/síntese química , Candida/efeitos dos fármacos , Proteínas Fúngicas/antagonistas & inibidores , Moduladores de Transporte de Membrana , Proteínas de Membrana Transportadoras/antagonistas & inibidores , Piperazinas/síntese química , Quinazolinas/síntese química , Antifúngicos/farmacologia , Candida/enzimologia , Farmacorresistência Fúngica , Sinergismo Farmacológico , Fluconazol/química , Fluconazol/farmacologia , Humanos , Técnicas In Vitro , Modelos Moleculares , Piperazinas/química , Piperazinas/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Solubilidade , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Structure-activity relationships of a novel series of fungal efflux pump inhibitors with respect to potentiation of the activity of fluconazole against strains of Candida albicans and Candida glabrata over-expressing ABC-type efflux pumps are systematically explored.