L-870,810: A potent antiviral HIV integrase inhibitor with potential clinical utility.
Int Conf AIDS 2002 Jul 7-12; 14:(abstract no. LbPeA9007)
Young S; Merck &Co., Inc, West Point, PA, United States
Current therapies available for treatment of HIV infection target only two of the three constitutive viral enzymes required for replication, namely the reverse transcriptase and protease. The third enzyme, HIV-1 integrase, is an attractive target for chemotherapeutic intervention in the treatment of AIDS in large part due to the absence of viruses harboring resistance to yet unknown integrase inhibitors. Unlike the reverse transcriptase and protease enzymes, successful drug candidates based on inhibition of integrase have yet to emerge. Previously, we disclosed a series of integrase inhibitors discovered through screening that have anti-replicative activity in cell culture. These leads come from a single class of molecules: 4-aryl-2,4-diketobutanoic acids (DKAs). While optimization of these leads produced DKA compounds with promising antiviral activity, concerns about their metabolic reactivity caused us to seek alternatives for the DKA pharmacophore. Replacement of critical elements of the pharmacophore led to a novel, metabolically stable series of heterocyclic compounds. These compounds are potent inhibitors of HIV-1 integrase strand transfer functionality. In cell culture the antiviral activity of these agents against wild type virus is similar to that of the more potent approved antiretroviral drugs. The antiviral activity of these compounds is undiminished against a variety of diverse clades and viral variants expressing significant resistance to all of the currently available licensed HIV-1 inhibitors, including PIs, NRTIs and NNRTIs. The leading compound, L-870,810, has good pharmacokinetics in rats, dogs and rhesus macaques. Its absolute oral bioavailability and half-life in these species, along with its stability in isolated human hepatocytes, suggests a high potential for good pharmacokinetics in humans. Following preliminary safety assessment studies, this compound has moved into Phase I clinical trials for evaluation in healthy volunteers.
Keywords: AEGIS, HIV Integrase Inhibitors, HIV Integrase, HIV-1, HIV Infections, RNA-Directed DNA Polymerase, Acquired Immunodeficiency Syndrome, Integrases, Dogs, Animal, Human, Rats
