Development of HIV protease inhibitors: a survey

In the treatment of infections caused by rapidly mutating viruses like human immunodeficiency virus (HIV), combination therapy with multiple drugs acting by different mechanisms offers several advantages over monotherapy. It may provide: synergistic effect, possible reduction of dosages and side-effects, and reduction of the chance of drug resistance. In the past few years, hundreds of HIV protease inhibitors have been synthesized and tested in order to overcome the limitations of reverse transcriptase inhibitors like zidovudine and others. In this review, emphasis is placed on the development of HIV protease inhibitors as antiviral agents against HIV, and structure-activity relationship analysis of saquinavir and related compounds. Limitations of some protease inhibitors and ways to overcome the shortcomings are presented. Among these many protease inhibitors five have been marketed during 1995-1999. They are saquinavir, ritonavir, indinavir, nelfinavir and amprenavir. Their different structural features, important physicochemical, pharmacokinetic and clinical profiles are presented in a table form for easy comparison. It is hoped that in the future new drugs based on additional mechanisms can be developed for the treatment of AIDS.