RESUMO
A novel antifungal strategy targeting the inhibition of calcineurin is described. To develop a calcineurin based inhibitor of pathogenic fungi, analogs of FK506 were synthesized that were able to permeate mammalian but not fungal cells. Antagonists in combination with FK506 were not immunosuppressive and retained antifungal activity in A. fumigatus. To reduce the dosage burden of the antagonist, murine oral PK was improved an order of magnitude relative to previous FK506 antagonists.
Assuntos
Antifúngicos/farmacologia , Inibidores de Calcineurina/farmacologia , Tacrolimo/análogos & derivados , Tacrolimo/farmacologia , Animais , Antifúngicos/síntese química , Antifúngicos/farmacocinética , Antifúngicos/toxicidade , Aspergillus fumigatus/efeitos dos fármacos , Inibidores de Calcineurina/síntese química , Inibidores de Calcineurina/farmacocinética , Inibidores de Calcineurina/toxicidade , Chlorocebus aethiops , Células Hep G2 , Humanos , Interleucina-2/metabolismo , Células Jurkat , Tacrolimo/síntese química , Tacrolimo/farmacocinética , Tacrolimo/toxicidade , Proteína 1A de Ligação a Tacrolimo/química , Células VeroRESUMO
Two novel series of oxazepine and diazepine based HSP90 inhibitors are reported. This effort relied on structure based design and isothermal calorimetry to identify small drug like macrocycles. Computational modelling was used to build into a solvent exposed pocket near the opening of the ATP binding site, which led to potent inhibitors of HSP90 (25-30).
Assuntos
Amidas/química , Benzodiazepinas/química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Indóis/química , Oxazepinas/química , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Amidas/metabolismo , Amidas/farmacologia , Animais , Azepinas/química , Benzamidas/química , Benzamidas/metabolismo , Benzodiazepinas/metabolismo , Benzodiazepinas/farmacologia , Sítios de Ligação , Permeabilidade da Membrana Celular/efeitos dos fármacos , Cristalografia por Raios X , Cães , Avaliação Pré-Clínica de Medicamentos , Proteínas de Choque Térmico HSP90/metabolismo , Indóis/metabolismo , Indóis/farmacologia , Células Madin Darby de Rim Canino , Simulação de Acoplamento Molecular , Oxazepinas/metabolismo , Oxazepinas/farmacologia , Ligação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , ortoaminobenzoatos/química , ortoaminobenzoatos/metabolismoRESUMO
C1 Nitrogen iminocyclitols are potent inhibitors of N-acetyl-beta-hexosaminidases. Given hexosaminidases' important roles in osteoarthritis, we developed two straightforward and efficient syntheses of C1 nitrogen iminocyclitols from two readily available starting materials, D-mannosamine hydrochloride and the microbial oxidation product of fructose. A diversity-oriented synthetic strategy was then performed by coupling these core structures with various aldehydes, carboxylic acids, and alkynes to generate three separate libraries. High-throughput screening of the generated libraries with human N-acetyl-beta-hexosaminidases produced only moderate inhibitory activities. However, the synthetic approach and screening strategy for these compounds will be applied to develop new potent inhibitors of human N-acetyl-beta-hexosaminidases, particularly when combined with the structural information of these enzymes.