U75875

Adaptation of the hydroxyethylamine dipeptide isostere to mimic the Phe-Pro site has produced inhibitors with selectivity for the retro viral protease (8.81, Ki=0.66 nM). Conversion of the proline to a decahydroisoquinoline nucleus has been very successful in the development of the potent selective HIV protease inhibitor saquinavir (8.82, Ki< 0.12 nM) which has recently gained licensing approval in USA for clinical use. Unlike compound JG-365 (8.83), where the crystal structure has shown a preferance for the (S)-hydroxyl enantiomer of the isostere fragment of the molecule, the R)-configuration is preferred for saquinavir (R-enantomer IC50=0.4 nM, S-enantomer IC50=>100 nM). X-ray crystallography studies have shown that the hydroxyl group is located between the aspartic acids in both JG-365 and saquinavir, but the adjacent methylene groups fit in a different manner into the active site.

SC 52151 (8.84, IC50=6.3 nM), based on hydroxyethylurea isostere has oral bioavailability. L 735 524 (8.85, IC50=0.36 nM), which is a combination of a

(ft.82): saquinavir
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