Nonpeptide inhibitors of HIV protease

Abstract Mass screening of our compound collection, utilizing the Amersham SPA technology, afforded pyrone and coumarin non-peptide templates as initial lead structures. X-ray cocrystallization and structure-based design were utilized to assist in the design of more potent inhibitors. These efforts resulted in the design of the 5,6-dihydropyrones, which afforded a more flexible template from which to fill the internal pockets of the enzyme. Optimization of the dihydropyrone series afforded a potent antiviral agent, PD 178390 (EC 50 =0.20 μM, TD 50 =>100 μM). PD 178390 retained antiviral potency in the presence of serum proteins with a modest three-to fivefold drop in antiviral activity in the presence of 40% human serum. The antiviral activity, in PBMCs, was unchanged against clinical strains of resistant HIV virus. In addition, PD 178390 showed excellent bioavailability in mice, rats, and dogs as well as a low level of P450 inhibition in microsomal assays. This combination of good antiviral efficacy, good pharmacokinetics, and low P450 inhibition make PD 178390 a promising agent for the treatment of HIV infection.

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