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hydroxyethylene isostere and a hydroxyethylamine isostere, is also orally active. The sulphonamido moiety, in the novel (R)-hydroxy ethyl sulphonamides isostere (8.86), has also been used to replace the P1'P2' amide linkage of the inhibitor (8.87, Ki=1 nM).

Symmetrical inhibitors (8.88, IC50=0.2 nM; 8.89, Ki=0.8 pM) capitalize on the unique symmetry of the homodimeric enzyme. Unlike transition-state analogues, the

stereochemistry of the two hydroxyl groups is not significant. Modifications to evaluate the effect of polar heterocyclic end groups led to the nonsymmetrical inhibitor A77003 (8.90, IC50<1 nM). Improved oral bioavailabilty was obtained with A 80987 (8.91, Ki= 0.25 nM) where the methylamide groups had been replaced by esters.

Penicillin-derived symmetrical dimers (8.92) have been identified as good lead structures from screening programmes. A hybrid of a penicillin derived structure and statine isostere shows good inhibitory activity (8.93, Ki=0.25 nM). The antipsychotic agent haloperidol (8.94, Ki=100 pM) was identified as a weak inhibitor through a computational search of a structural database based on a complementary shape of the HIV-1 protease active site. The 1,3-dithiolane analogue (8.95, K=15 pM) exhibits greater inhibitory potency.

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