5,6,7,8-Tetrahydro-1,6-naphthyridine Derivatives as Potent Allosteric Site HIV-1 Integrase Inhibitors.

A series of 5,6,7,8-tetrahydro-1,6-naphthyridine derivatives targeting the allosteric lens epithelium-derived growth factor (LEDGF) binding site on HIV-1 integrase was prepared and screened for activity against HIV-1 infection in cell culture. HIV-1 integrase, one of three enzymes encoded in the viral genome, presents an attractive target for antiviral chemotherapy. Small molecules that bind within the LEDGF binding site promote aberrant multimerization of the integrase enzyme and are of significant interest as a new class of HIV-1 replication inhibitors. SAR studies of the 5,6,7,8-tetrahydro-1,6-naphthyridine series that led to identification of an N-propyl phenyl group as a preferred substituent are presented. Lead compounds from the series were profiled in rat pharmacokinetic studies.