These compounds are new protease inhibitors under development by Bristol-Myers Squibb. They are known to be active in the test tube against viruses constructed from clinical isolates derived from patients with high level protease inhibitor resistance.

A virus with mutations at codons 10, 63, 71, 82, 84 and 90 proved highly resistant to other HIV protease inhibitors (13-190-fold loss of sensitivity), but showed only a marginal loss of sensitivity to DPC 681 or DPC 683. Viruses derived from patients on failing PI-containing regimens were suppressed vitro at concentrations of 10 to 11 nM by DPC 681 and 684, compared to concentrations of 77nM for lopinavir, the PI currently considered most potent against PI-resistant virus. However, the maximum tolerable dose of each compound has not been defined, and the apparent potency of these agents may be limited by a lower tolerability threshold (Bacheler).

Human studies in Europe and the United States to test the safety and effectiveness of DPC 684 were stopped after cardiac problems were observed. The development of DPC 684 has now ceased.

Reference

Bacheler LT et al. Resistance profiles of second generation HIV protease inhibitors DPC 681 and DPC 684. Antiviral Therapy 6 (supp1): 5-6, 2001.

Erickson-Viitanen S et al. DPC 681 and DPC 684: resistance and cross-resistance profiles of second generation protease inhibitors. Eighth Annual Conference on Retroviruses, abstract 11, 2001.

Kaltenbach RF et al. DPC 681 and DPC 684: potent, selective inhibitors of human immunodeficiency virus protease active against clinically relevant mutant variants. Antimicrobial Agents and Chemotherapy 45(11):3021-3018, 2001.