Synthesis and structure-activity-relationships of 1H-imidazo[4,5-c]quinolines that induce interferon production.

1H-Imidazo-[4,5-c]quinolines were prepared while investigating novel nucleoside analogues as potential antiviral agents. While these compounds showed no direct antiviral activity when tested in a number of cell culture systems, some demonstrated potent inhibition of virus lesion development in an intravaginal guinea pig herpes simplex virus-2 assay. We have determined that the in vivo antiviral activity can be attributed to the ability of these molecules to induce the production of cytokines, especially interferon (IFN), in this model.

The immune response modifiers imiquimod and R-848 are potent activators of B lymphocytes.

Imiquimod and R-848 are members of a family of immune response modifiers that stimulate cytokine production in monocyte/macrophages and dendritic cell cultures. This study evaluated the effects of the imidazoquinolines, imiquimod and R-848, on B lymphocyte activation. Both agents induced proliferation of murine T-cell-depleted and highly purified splenic B cell preparations as well as purified human B cells.

Treatment of primary herpes simplex virus infection in guinea pigs by imiquimod.

Imiquimod (also known as R-837 and S-26308) is an imidazoquinoline immune response modifier and is available in the US and several other countries for the treatment of external genital warts. Imiquimod has no direct antiviral activity but demonstrates efficacy in several animal models of virus infection. The drug is recognized by antigen presenting cells including monocytes, macrophages, B-cells and dendritic cells and induces these cells to produce cytokines including interferon-alpha (IFN-alpha) and others.

Cytokine induction in hairless mouse and rat skin after topical application of the immune response modifiers imiquimod and S-28463.

ALDARA (imiquimod cream 5%) recently became available for the treatment of genital and perianal warts; however, the topical mechanism of action of imiquimod is not fully understood. Imiquimod, and its analogs R-842, S-27609, and S-28463, are potent anti-viral and anti-tumor agents in animal models. Much of the biologic activity of these compounds can be attributed to the induction of cytokines, including interferon-alpha, tumor necrosis factor-alpha, interleukins-1, -6, -8, and others.

Induction of cytokines in cynomolgus monkeys by the immune response modifiers, imiquimod, S-27609 and S-28463.

Imiquimod, S-27609 and S-28463 are imidazoquinolines known to have antiviral and antitumour properties mediated by the induction of cytokines, in particular interferon alpha (IFN-alpha). This study evaluated these compounds for their ability to induce cytokines and cytokine specific messenger RNAs (mRNA) in cynomologus monkeys (Macaca fascicularis). Peripheral blood mononuclear cell (PBMC) cultures from monkeys produced IFN, interleukin 1beta (IL-1beta), IL-6 and IL-8 after treatment with imiquimod, S-27609 and S-28463.