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An agent that is unique among Pi's in clinical development is tipranavir (PNU-140690) (16), a compound evolved from a non-peptide screening lead that does not employ a hydroxylic transition state mimic in its backbone (39). As such, clinical resistance to tipranavir comes from amino acid substitution patterns in protease that differ somewhat from those elicited by conventional Pi's. Typical mutations in protease that engender resistance to tipranavir include the relatively uncommon changes at residues 82(V-T) and 90(L-M) (40). Tipranavir has modest innate pharmacokinetics in man, and therefore requires co-dosing or "boosting" with the P450 inhibitory PI ritonavir to maintain adequate trough levels.

The combination of the two Pi's shows potent antiviral activity in treatment experienced patients (41). Two new Pi's based on more conventional backbones have entered phase I clinical trials. DPC-681 (17) and DPC-684 (18) are arylsulfonamidohydroxyethylamine transition state isosteres with low nanomolar antiviral activity (IC^'s = 4-40 nM, wild type HIV) and superior resistance profiles (42). A notable feature of these compounds is their extraordinary inhibitory activity against purified enzyme. Ki's for wild type protease are 12 and 21 pM for 17 and 18 respectively, potencies in line with the clinically effective PI lopinavir (43). Also of current interest in the PI field is the phosphate prodrug of amprenavir, known as fosamprenavir (GW433908). Fosamprenavir has significantly improved oral bioavailability in man relative to the parent drug. The increased aqueous solubility of the phosphate allows for better formulation and a lower pill burden, two 700 mg tablets are equivalent to eight amprenavir capsules (44). Regulatory approval of fosamprenavir is anticipated in 2003.

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