The optimal characteristics of a new protease inhibitor (PI) would include high intrinsic potency, activity against PI-resistant viruses, excellent gastrointestinal tolerability and minimal effects on plasma lipids. This study describes efforts by Abbott Laboratories to design such a compound.

The strategy involved combining a PI compound that had potent activity against resistant viruses with a segment of atazanavir (ATV, Reyataz), which is known to have neutral effects on lipids.

The resulting compound, called A-681799, showed potent activity against viruses resistant to atazanavir, even in the presence of 50% human serum. In addition, pharmacokinetic studies in rats and dogs showed adequate levels to theoretically allow for once-daily dosing, especially in the presence of low-dose ritonavir (RTV, Norvir).

Other favorable characteristics included relatively low protein binding and modest inhibition of CYP3A4 enzymes. However, in a rat model designed to test for unconjugated hyperbilirubinemia, this compound was found to significantly elevate bilirubin levels. As a result, further clinical development of A-681799 has been stopped in favor of other candidates they hope will be more promising.

The importance of this study relates not necessarily to the specific qualities of the novel PI cited here -- the vast majority of investigational agents never make it to clinical trials -- but to the elucidation of the process by which ideal new compounds are developed. It is encouraging that this particular drug development team is moving forward with additional PIs, as its extensive experience with PIs gives both its scientific and clinical groups a good sense of the priorities in the field.