ABSTRACT:
BMS 232,632 is an HIV-1 protease inhibitor belonging to the azapeptide class of peptidomimetic inhibitors and is currently undergoing evaluation in Phase II clinical trials. BMS 232,632 displays potent and selective antiviral activity (EC50 25 µM) in a variety of cell types using several HIV isolates. The combination of potency and excellent pharmacokinetic parameters support its potential for once daily oral dosing. The resistance profile of BMS 232,632 was assessed in reciprocal cross-resistance studies. Results showed that strains resistant to the five currently approved protease inhibitors retained significant sensitivity to BMS 232,632, suggesting that BMS 232,632 may provide coverage of isolates showing low-level resistance to other protease inhibitors. Variants resistant to BMS 232,632 were generated by passage of three different strains (RF, BRU and NL4-3) of HIV-1 in the presence of increasing concentrations of inhibitor.
Phenotypic testing showed that highly resistant (79- to 188-fold) variants of all three strains could be generated over a period of up to 4.8 months. Genotypic analysis indicated that high-level resistance could only be achieved through a series of multiple mutations, which appeared to be somewhat different for each strain. An N88S substitution appeared early in two of the three strains and may be the signature mutation for this inhibitor. I84V and L89M mutations appeared to be important in the third strain. Similar to other HIV-1 protease inhibitors, cleavage site mutations were also observed in the BMS 232,632-selected variants. A cross-resistance study involving the other five protease inhibitors indicated that the BMS 232,632 resistant variants displayed partial cross resistance (Strain dependent) to other protease inhibitors. Taken together, the data suggest that BMS 232,632 is a new generation of HIV protease inhibitor that should be a valuable addition to our anti-HIV armamentarium.
