A rational drug design strategy using crystallographic information generated from several HIV Protease-inhibitor complexes has led to the discovery of a novel series of highly potent, non-peptidic and cyclic inhibitors of the HIV protease. The new structure of these compounds possesses a C(2) symmetric diol which resembles the transition state of the enzyme-catalyzed reaction. In addition, the complete lack of the amide functionality in the structure prevents these molecules from proteolytic cleavage. The structural water in the active site was displaced by the oxygen atom of the SO(2) group in the cyclic scaffold. The side chains of the cyclic structure occupy only S(1)(S(1)) and S(2)(S(2)) regions of the enzyme active site. Those structural features are different from HIV protease inhibitors described previously. One member of this class, GS 3333 (Ki less than 1 nM, IC(90)=40 nM in MT2 cells) was selected for further evaluation of pharmacokinetics and oral bioavailability. A single 10 mg/kg oral dose of GS 3333 administered to dogs (n=5/group) gave the following pharmacokinetic profiles: F=74%, C(max)=3.3 micrograms/mL, t(1/2)=4.7h. The duration that the plasma drug concentration remained 20 times above IC(90) exceeded 12 hours. Preliminary structure activity relationships will also be presented.

*HIV Protease Inhibitors/CHEMICAL SYNTHESIS *Sulfones/CHEMISTRY

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