RESUMEN

We report the synthesis of benzoazepine-derived cyclic malonamides (2) and aminoamides (3) as gamma-secretase inhibitors for the potential treatment of Alzheimer's disease. The in vitro structure-activity relationships of 2 and 3 along with dog pharmacokinetic results are described.

Asunto(s)

Amidas/farmacología , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Azepinas/química , Azepinas/farmacología , Azepinas/síntesis química , Ciclización , Modelos Moleculares , Relación Estructura-Actividad

RESUMEN

The synthesis, evaluation, and structure-activity relationships of a series of succinoyl lactam inhibitors of the Alzheimer's disease gamma-secretase are described. Beginning with a screening hit with broad proteinase activity, optimization provided compounds with both high selectivity for inhibition of gamma-secretase and high potency in cellular assays of A beta reduction. The SAR and early in vivo properties of this series of inhibitors will be presented.

Asunto(s)

Caprolactama/química , Endopeptidasas/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Succinatos/química , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/enzimología , Secretasas de la Proteína Precursora del Amiloide , Animales , Ácido Aspártico Endopeptidasas , Caprolactama/análogos & derivados , Línea Celular , Perros , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Endopeptidasas/química , Inhibidores Enzimáticos/química , Humanos , Conformación Molecular , Estereoisomerismo , Relación Estructura-Actividad