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1.
ACS Med Chem Lett ; 5(3): 264-9, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-24900818

RESUMO

We have previously reported the discovery of our P2-P4 macrocyclic HCV NS3/4a protease inhibitor MK-5172, which in combination with the NS5a inhibitor MK-8742 recently received a breakthrough therapy designation from the US FDA for treatment of chronic HCV infection. Our goal for the next generation NS3/4a inhibitor was to achieve pan-genotypic activity while retaining the pharmacokinetic profile of MK-5172. One of the areas for follow-up investigation involved replacement of the quinoxaline moiety in MK-5172 with a quinoline and studying the effect of substitution at 4-position of the quinoline. The rationale for this effort was based on molecular modeling, which indicated that such modifications would improve interactions with the S2 subsite, in particular with D79. We wish to report herein the discovery of highly potent inhibitors with pan-genotypic activity and an improved profile over MK-5172, especially against gt-3a and A156 mutants.

2.
J Med Chem ; 49(4): 1455-65, 2006 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-16480282

RESUMO

Novel Gram-positive (Gram+) antibacterial compounds consisting of a DNA polymerase IIIC (pol IIIC) inhibitor covalently connected to a topoisomerase/gyrase inhibitor are described. Specifically, 3-substituted 6-(3-ethyl-4-methylanilino)uracils (EMAUs) in which the 3-substituent is a fluoroquinolone moiety (FQ) connected by various linkers were synthesized. The resulting "AU-FQ" hybrid compounds were significantly more potent than the parent EMAU compounds as inhibitors of pol IIIC and were up to 64-fold more potent as antibacterials in vitro against Gram+ bacteria. The hybrids inhibited the FQ targets, topoisomerase IV and gyrase, with potencies similar to norfloxacin but 10-fold lower than newer agents, for example, ciprofloxacin and sparfloxacin. Representative hybrids protected mice from lethal Staphylococcus aureus infection after intravenous dosing, and one compound showed protective effect against several antibiotic-sensitive and -resistant Gram+ infections in mice. The AU-FQ hybrids are a promising new family of antibacterials for treatment of antibiotic-resistant Gram+ infections.


Assuntos
Compostos de Anilina/síntese química , Antibacterianos/síntese química , DNA Polimerase III/antagonistas & inibidores , Bactérias Gram-Positivas/efeitos dos fármacos , Inibidores da Topoisomerase II , Uracila/análogos & derivados , Uracila/síntese química , Compostos de Anilina/farmacocinética , Compostos de Anilina/farmacologia , Animais , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Farmacorresistência Bacteriana , Masculino , Camundongos , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Testes de Toxicidade Aguda , Uracila/farmacocinética , Uracila/farmacologia
3.
Bioorg Med Chem Lett ; 12(8): 1181-4, 2002 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-11934583

RESUMO

The potency and selectivity of a previous series of low molecular weight thrombin inhibitors were improved through modifications of the P1 and P3 residues. Introduction of diphenyl substituted sulfonamides in the P3 moiety led to highly efficacious compounds. By correctly selecting the combination of P1 and P3 residues, high levels of potency, selectivity and in vivo efficacy were obtained.


Assuntos
Antitrombinas/farmacologia , Lactamas/farmacologia , Antitrombinas/química , Lactamas/química
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