HIV-1 Protease Nonpeptide Inhibitors

In recent years a number of potent peptidomimetic inhibitors of HIV-1 protease have been reported in the literature. One highly potent series was designed to be symmetric molecules to complement the enzyme [60] (Fig. 10). However, as with renin inhibitors, these analogs often carry with them the properties associated with peptides low cellular activity and poor oral bioavailability. The quest, therefore, for a nonpeptide inhibitor again became the focus of our efforts as well as that of numerous other laboratories. In contrast to the renin studies. 

3 Structure-Based Design From Renin to HIV-1 Protease 

Simultaneously, the advanced technology of mass screening was applied to an extensive chemical database [70], This process resulted in numerous hits including the coumarin and pyrone, 29 and 30, shown in Table 6. Both inhibitors exhibited micromolar potency. Because of their small size, achiral nature and their inhibitory activity, they became the prototypes for biological and chemical studies as well as for X-ray determination. The mass screening approach was also applied elsewhere and resulted in a very similar warfarin hit [71]. In both cases, the initial micromolar leads were elaborated to potent inhibitors through structure- 

Since the coumarin structure occupied fewer pockets than the pteptidomimetic analogs (Fig. 14) and the two binding modes in the crystal structure showed that the coumarin side chain could occupy two separate binding sites, the concept of branching the phenoxy side chain was pursued. This resulted in 32, which incorporated a nitrogen at the branching point 

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