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
The design of a new clinical candidate histamine-H(3) receptor antagonist for the potential treatment of excessive daytime sleepiness (EDS) is described. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were modified by replacement of the sulfonamide linkage with a sulfone. One compound from this series, 2j (APD916) increased wakefulness in rodents as measured by polysomnography with a duration of effect consistent with its pharmacokinetic properties. The identification of a suitable salt form of 2j allowed it to be selected for further development.