HIV integrase inhibitors: from diketoacids to heterocyclic templates: a history of HIV integrase medicinal chemistry at Merck West Point and Merck Rome (IRBM).

Replication of the human immunodeficiency virus (HIV) is dependent upon the enzyme HIV integrase (IN), one of three essential enzymes encoded in the viral genome. HIV-1 IN catalyzes the insertion of the proviral DNA into the host genome (strand transfer). HIV-1 IN therefore presents an attractive chemotherapeutic target for the treatment of HIV infection and AIDS that could provide patients and physicians with an additional option for treatment. Assays were developed to identify inhibitors of IN strand transfer. Diketoacid lead compounds were explored and developed into a variety of heterocyclic templates that are potent inhibitors of integrase strand transfer with suitable medicinal chemical properties for treating HIV infection and AIDS. The 1,6-naphthyridine L-870810 (Antiviral activity in cells IC(95) NHS = 102 nM, n=237), was shown to be efficacious in reducing viral RNA by 1.7 log units after doses of 400mg BID to HIV infected patients. Optimization of physical properties led to L-900564, an inhibitor of HIV IN that has excellent cell potency in the presence of protein (Antiviral activity in cells IC(95) NHS = 16 nM, n=15), excellent activity against mutants raised to HIV integrase inhibitors, and a very good pharmacokinetic profile.

A historical sketch of the discovery and development of HIV-1 integrase inhibitors.

The long process of HIV-1 integrase inhibitor discovery and development can be attributed to both the complexity of HIV-1 integration and poor 'integration' of these researches into mainstream investigations on antiretroviral therapy in the mid-1990s. Of note, some fungal extracts investigated during this period contain the beta-hydroxyketo group, later recognised to be a key structural requirement for keto-enol acids (also referred to as diketo acids) and other integrase inhibitors. This review reconstructs (in the general context of the history of AIDS research) the principal steps that led to the integrase inhibitors currently in clinical trials, and discusses possible future directions.