Potent inhibitors of the HIV-1 protease with good oral bioavailabilities.

A series of novel pseudo-symmetrical and unsymmetrical inhibitors based on the backbone modification of a peptidomimetic were synthesized and found to be highly potent inhibitors of the HIV-1 protease (IC50 = 2.9 to < 0.5 nM). These compounds also possess good antiviral activity in vitro as measured by inhibition of the cytopathic effect of HIV-1(3B) in MT-4 lymphocytes. Importantly, some of these compounds also have good oral bioavailabilities in rats (F = 30.6% to 100%). One of these compounds 4C, also has good oral bioavailability in beagle dogs and cynomolgus monkeys.