RESUMO
A series of hK6 inhibitors with a para-amidobenzylamine P1 group and a 2-hydroxybenzamide scaffold linker was discovered through virtual screening. The X-ray structure of hK6 complexed with compound 9b was determined to a resolution of 1.68Å. The tertiary folding of the hK6 complexed with the inhibitor is conserved relative to the structure of the apo-protein, whereas the interaction between hK6 and the inhibitor is consistent with both the SAR and the in silico model used in the virtual screening.
Assuntos
Benzamidas/química , Benzilaminas/química , Calicreínas/química , Modelos Moleculares , Inibidores de Serina Proteinase/química , Benzilaminas/farmacologia , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Humanos , Calicreínas/antagonistas & inibidores , Ligação Proteica , Dobramento de Proteína , Estrutura Terciária de Proteína , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of compounds with an amidinothiophene P1 group and a pyrrolidinone-sulphonamide scaffold linker was identified as potent inhibitors of human kallikrein 6 by structure-based virtual screening based on the union accessible binding space of serine proteases. As the first series of potent nonmechanism-based hK6 inhibitors, they may be used as tool compounds for target validation. An X-ray structure of a representative compound complexed with hK6, resolved at a resolution of 1.88 Å, revealed that the amidinothiophene moiety bound in the S1 pocket and the pyrrolidinone-sulphonamide linker projected the aromatic tail into the S' pocket.
RESUMO
Teriflunomide is an orally available anti-inflammatory drug that prevents T and B cell proliferation and function by inhibition of dihydroorotate dehydrogenase. It is currently being developed for the treatment of multiple sclerosis (MS). We report here for the first time the anti-inflammatory effects of teriflunomide in the Dark Agouti rat model of experimental autoimmune encephalomyelitis (EAE). Neurological evaluation demonstrated that prophylactic dosing of teriflunomide at 3 and 10 mg/kg delayed disease onset and reduced maximal and cumulative scores. Therapeutic administration of teriflunomide at doses of 3 or 10 mg/kg at disease onset significantly reduced maximal and cumulative disease scores as compared to vehicle treated rats. Dosing teriflunomide at disease remission, at 3 and 10 mg/kg, reduced the cumulative scores for the remaining course of the disease. Teriflunomide at 10 mg/kg significantly reduced inflammation, demyelination, and axonal loss when dosed prophylactically or therapeutically. In electrophysiological somatosensory evoked potential studies, therapeutic administration of teriflunomide, at the onset of disease, prevented both a decrease in waveform amplitude and an increase in the latency to waveform initiation in EAE animals compared to vehicle. Therapeutic dosing with teriflunomide at disease remission prevented a decrease in evoked potential amplitude, prevented an increase in latency, and enhanced recovery time within the CNS.