Synthesis and Evaluation of a Novel Anti-HIV Agent

The long-term goal of this research is to develop a drug that is safe and effective against drug-resistant human immunodeficiency virus (HIV) infection. Several challenges confront current anti-HIV chemotherapy. The frequency of drug-resistant and multidrug-resistant HIV-1 is increasing. Toxicities associated with current HIV medications often result in the discontinuation of these therapies. Physicians are often left with few anti-HIV drugs to prescribe once resistance and/or toxicities develop in patients. Potent drugs with novel mechanisms of action, activity against resistant HIV, and with reduced toxicity are needed. KPC-2 is an anti-HIV compound with a mechanism of action distinct from existing HIV therapies. In vitro studies indicate that it has potent activity against HIV including activity against drug-resistant and multidrug-resistant HIV. The purpose of this Phase II SBIR application is to further develop KPC-2 by completing key preclinical studies. The specific aims of this project include the evaluation KPC-2 activity in an HIV SCID mouse model, the scale-up synthesis of KPC-2, determination of KPC-2 plasma protein binding in human and animal plasma, in vitro metabolism studies of KPC-2, development of a stability-indicating HPLC assay, completion of stability studies, and the completion of pharmacology and toxicology studies of KPC-2 in rats and monkeys. The successful completion of these proposed studies should enable the Kucera Pharmaceutical Company to quickly move the development of this novel compound into human clinical trials.