HIV integrase is essential for HIV replication. However, there are currently no integrase inhibitors in clinical use for AIDS. We have discovered a conceptually new β-diketo acid that is a powerful inhibitor of both the 3′-processing and strand transfer steps of HIV-1 integrase. The in vitro anti-HIV data of this inhibitor were remarkable as exemplified by its highly potent antiviral therapeutic efficacy against HIV TEKI and HIV-1 NL4-3 replication in PBMC (TI >4,000 and >10,000, respectively).

HIV-1 integrase is a protein of Mr 32 000 encoded at the 3'-end of the pol gene. Integration of HIV DNA into the host cell chromosomal DNA apparently occurs by a carefully defined sequence of DNA tailoring (3'-processing (3'P)) and coupling (integration) reactions. Integration of HIV DNA into human DNA represents the biochemical completion of the invasion of the human cell (e.g., T-cell) by HIV. Unlike major successes seen in the development of clinically approved anti-HIV agents against HIV reverse transcriptase and HIV protease, there are no FDA-approved anti-HIV drugs in clinical use where the mechanism of action is inhibition of HIV integrase. This review summarises some key advances in the area of integrase inhibitors with the major focus being on new generation inhibitors. Special emphasis is placed on diketo acids with aromatic and heteroaromatic moieties, diketo acids with nucleobase scaffolds, bis-diketo acids, functionalised naphthyridines and other isosteres of diketo acids. Data pertaining to integrase inhibition and in vitro anti-HIV activity are discussed. Mention is made of drugs in clinical trials, both past (S-1360, L-870,810 and L-870,812 and present (GS-9137 and MK-0518). Other promising drugs, including those from the authors' laboratory, are referred. Resistant mutants arising from key integrase inhibitors and cross-resistance are indicated.

Worldwide research efforts in drug discovery involving HIV integrase have produced only one compound, raltegravir, that has been approved for clinical use in HIV/AIDS. As resistance, toxicity and drug-drug interactions are recurring issues with all classes of anti-HIV drugs, the discovery of novel integrase inhibitors remains a significant scientific challenge. We have designed a lead HIV-1 strand transfer (ST) inhibitor (IC50 70 nM), strategically assembled on a pyridinone scaffold. A focused structure-activity investigation of this parent compound led to a significantly more potent ST inhibitor, 2 (IC50 6 ± 3 nM). Compound 2 exhibits good stability in pooled human liver microsomes. It also displays a notably favorable profile with respect to key human cytochrome P450 (CYP) isozymes and human UDP glucuronosyl transferases (UGTs). The prodrug of inhibitor 2, i.e., compound 10, was found to possess remarkable anti-HIV-1 activity in cell culture (EC50 9 ± 4 nM, CC50 135 ± 7 μM, therapeutic index = 15,000).