Combinatorial Synthesis of Hiv1 Integrase Inhibitors

Period of Performance: 07/01/1999 - 12/31/1999


Phase 1 SBIR

Recipient Firm

Medichem Research, Inc.
Lemont, IL 60439
Principal Investigator


Treatment of AIDS is currently limited to inhibitors of the human immunodeficiency virus (HIV) enzymes protease and reverse transcriptase. Integrase plays a critical role in the life cycle of HIV, and is a prime target for a new class of inhibitors. One very attractive feature about integrase is that there is no known human analogue for this enzyme. Integrase inhibitors are not currently used in the treatment of AIDS, reasons for this are due to the fact that most of the compounds tested thus far is either too toxic or are inactive against the integrase enzyme. The goal of this Phase I investigation is to build a library of compounds from a known active integrase inhibitor. Using molecular modeling, construct a library consisting of 14,520 compounds, and perform a diversity on the library and reduce the number to 864 of the most diverse compounds to be synthesized. Active analogues will be resynthesized in larger quantities using classical techniques to allow full physical and spectral characterization. Libraries will be screened for integrase inhibition using Amersham's HIV integrase SPA enzyme assay. POTENTIAL COMMERCIAL APPLICATIONS: Currently there are no inhibitors of HIV integrase available for clinical use. Recent encouraging results regarding combination therapy of HIV infection with reverse transcriptase and protease inhibitors underscore the promise that new agents operating via novel mechanisms could, in combination with existing agents, drastically alter the prognosis of infected persons. The market potential for a clinically useful integrase inhibitor is enormous, since recent studies estimate that over 17 million persons are infected with HIV worldwide.