RESUMEN

Incorporation of a gamma-lactam in hydroxyethylene isosteres results in modest inhibitors of HIV-1 protease. Additional structural activity studies have produced significantly more potent inhibitors with the introduction of the trisubstituted cyclopentane (see compound 20) as the optimum substituent for the C-terminus. This new amino acid amide surrogate can be readily prepared in large scale from (R)-pulegone. Optimized compounds (36) and (60) are potent antiviral agents and are well absorbed (15-20%) in a dog model after oral administration.

Asunto(s)

Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/farmacología , Lactamas/síntesis química , Lactamas/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Fenómenos Químicos , Química Física , Perros , Inhibidores de la Proteasa del VIH/farmacocinética , VIH-1/efectos de los fármacos , VIH-1/enzimología , Humanos , Lactamas/farmacocinética , Masculino , Modelos Moleculares , Relación Estructura-Actividad