RESUMO
We describe the development of cell-permeable beta-secretase inhibitors that demonstratively inhibit the production of the secreted amino terminal fragment of an artificial amyloid precursor protein in cell culture. In addition to potent inhibition in a cell-based assay (IC50 < 100 nM), these inhibitors display impressive selectivity against other biologically relevant aspartyl proteases.
Assuntos
Ácido Aspártico Endopeptidases/antagonistas & inibidores , Etilaminas/síntese química , Sulfonamidas/síntese química , Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases/química , Sítios de Ligação , Linhagem Celular , Permeabilidade da Membrana Celular , Cristalografia por Raios X , Desenho de Fármacos , Etilaminas/química , Etilaminas/farmacologia , Humanos , Modelos Moleculares , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
The highly pyramidalized alkene, pentacyclo[4.3.0.0(2,4).0(3,8).0(5,7)]non-4-ene (9), has been generated via treatment of 4,5-diiodopentacyclo[4.3.0.0(2,4).0(3,8).0(5,7)]nonane (12) with n-butyllithium and tert-butyllithium. The title alkene has also been trapped as its Diels-Alder adduct with 1,3-diphenylisobenzofuran, 2,5-dimethylfuran, and spiro[2.4]hepta-4,6-diene. Products resulting from alkyllithium addition to the pyramidalized double bond of 9 have been isolated and fully characterized spectroscopically. The geometry, olefin strain energy, heat of hydrogenation, and relative HOMO/LUMO energies of 9 have been obtained by ab initio calculations at the MP2 and B3LYP levels using the 6-31G* basis set.