HIV protease inhibitors with picomolar potency against PI-resistant HIV-1 by extension of the P3 substituent

Article abstract of DOI:10.1016/S0960-894X(03)00475-X

A biaryl pyridylfuran P₃ substituent on the hydroxyethylene isostere scaffold affords HIV protease inhibitors (PI's) with picomolar (IC₅₀) potency against the protease enzymes from PI-resistant HIV-1 strains. Inclusion of a gem-dimethyl substituent afforded compound 3 with 100% oral bioavailability (dogs) and more than double the t_1/2 of indinavir. Inhibition of multiple P450 isoforms is dependent on the regiochemistry of the pyridyl nitrogen in these compounds.