RESUMO
The bisamide class of kinase inhibitors was identified as being active against CSF-1R. The synthesis and SAR of pyridyl and thiazolyl bisamides are reported, along with the pharmacokinetic properties and in vivo activity of selected examples.
Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Tiazóis/farmacologia , Células 3T3 , Amidas/química , Amidas/farmacocinética , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Feminino , Humanos , Camundongos , Camundongos Nus , Ratos , Receptor de Fator Estimulador de Colônias de Macrófagos/genética , Tiazóis/química , Tiazóis/farmacocinéticaRESUMO
Through high throughput screening of various libraries, substituted styryl naphthalene 6 was identified as an HCMV protease inhibitor. Optimization of various regions of the lead molecule using parallel synthesis resulted in 1,6-substituted naphthalenes 19d-i. These compounds displayed good potency and were selective over elastase, trypsin, and chymotrypsin. The optimization approach on lead compound 6 in three different regions of the molecule using parallel solution-phase synthesis and the corresponding SAR are discussed in detail.
Assuntos
2-Naftilamina/síntese química , Citomegalovirus/química , Naftalenos/síntese química , Inibidores de Proteases/síntese química , Serina Endopeptidases/química , Sulfonamidas/síntese química , 2-Naftilamina/análogos & derivados , 2-Naftilamina/química , Bases de Dados Factuais , Naftalenos/química , Inibidores de Proteases/química , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
Herpesviruses encode a serine protease that is essential for the maturation of infectious virions. This protease has a unique polypeptide backbone fold and contains a novel Ser-His-His catalytic triad. It exists in a monomer-dimer equilibrium in solution, but only the dimer form of the enzyme is catalytically active. The stability of this dimer is affected by the presence of anti-chaotropic agents. Most of the reported Kd values for this dimer (between 0.6 and 6 microM) are inconsistent with the fact that the protease is routinely assayed at 20-50 nM concentrations, as only monomeric species would be expected with such Kd values. We have characterized the monomer-dimer equilibrium of HCMV protease using a new method, which observes the exchange between dimers of the wild-type enzyme and the active-site Ser132Ala mutant in a titration experiment. The Kd of the dimer was determined to be 8 microM and 31 nM in the absence or presence of anti-chaotropic agents (10% glycerol and 0.5 M Na2SO4), respectively. Detailed kinetic analysis also showed that, in addition to the 260-fold stabilization of the dimer, the anti-chaotropic agents produced a 7-fold enhancement in the catalytic activity of the dimer.
