The structure-activity relationships in two series of novel, symmetry-based inhibitors of HIV protease, the enzyme responsible for maturation of the human immunodeficiency virus, are described. Beginning with lead compounds 3-6, the effect of adding polar, heterocyclic end groups to one or both ends of the symmetric or pseudosymmetric inhibitors was probed. Aqueous solubility was enhanced > 1000-fold while maintaining potent inhibition of purified HIV-1 protease and anti-HIV activity in vitro. Pharmacokinetic studies in rats indicated a substantial difference in the absorption properties of mono-ol-based and diol-based inhibitors. The oral bioavailability of inhibitor 19 in rats was 19%; however, the Cmax obtained failed to exceed the anti-HIV EC50 in vitro. Substantial plasma levels of potent inhibitors of the diol class were not obtained after oral administration in rats; however, the optimal combination of aqueous solubility and in vitro antiviral activity of several inhibitors support their potential use in intravenous therapy.