Potent and Orally Bioavailable HIV-1 Proteinase Inhibitors Containing the 2-aminobenzylstatine Moiety

Abstract

In order to design HIV proteinase inhibitors which combine antiviral potency in HIV-infected cells with good oral bioavailability, new derivatives of 2-aminobenzylstatine containing HIV-1 proteinase inhibitors were synthesized. Compounds showing the desired profile emerged from a series of modifications at the P3′ moiety of the parent inhibitor [1], and are characterized by the presence of hydroxy or methoxy substituents at the C-terminal benzylamide. The most potent congeners, compounds [15] and [19], were evaluated in more detail and proved inhibitory to HIV-1 replication in primary T4 lymphocytes with EC₉₀= 2.2 and 2.7 nM, respectively. They also exhibited adequate oral bioavailability in the range of [13] to 42% in mice and rats. Thus, further investigation of this type of HIV proteinase inhibitor seems warranted.