Toll-like receptors (TLRs) are key targets in the design of immunomodulating agents for use as vaccine adjuvants and anticancer treatments. The imidazoquinolines, imiquimod and resiquimod, have been shown to activate TLR-7 and -8 which in turn induce cytokine production as part of the innate immune response. Herein, we report the synthesis and discovery of a C7-methoxycarbonyl derivative of imiquimod that stimulates cytokine production but is devoid of TLR-7/8 activity. Data is presented that shows this analog not only induces IL-12p40 and TNF production, similar to that of imiquimod and resiquimod, but greatly enhances the production of IL-1β, a key cytokine involved in activation of CD4 T cells. It is further demonstrated that TLR-7/8 activation can be recovered by the addition of a C2-alkyl substituent to this newly discovered analog. The results support the existence of an alternative mechanism of action by which imidazoquinolines can stimulate cytokine production.

27 Jul 2009·Journal of Chemical Information and ModelingQ2 · CHEMISTRY

Small-Molecule Interferon Inducers. Toward the Comprehension of the Molecular Determinants through Ligand-Based Approaches

Q2 · CHEMISTRY

Article

Author: Musmuca, Ira ; Ragno, Rino ; Simeoni, Silvia ; Caroli, Antonia

Hepatitis C is becoming an increasingly common cause of mortality especially in the HIV-coinfected group. Due to the efficacy of interferon (IFN) based therapy in the treatment of hepatitis C, various compounds possessing IFN-inducing activity have been hitherto reported. In the present study, we describe how steric, electrostatic, hydrophobic, and hydrogen-bonding interactions might influence the biological activity of a published set of IFN inducers, using a three-dimensional quantitative structure-activity relationship (3-D QSAR) approach. Analyses were conducted evaluating different series of compounds structurally related to 8-hydroxyadenines and 1H-imidazo[4,5-c]quinolines. A ligand-based alignment protocol in combination with the GRID/GOLPE approach was applied: 62 3-D QSAR models were derived using different GRID probes and several training sets. Performed 3-D QSAR investigations proved to be of good statistical value displaying r2, q2CV-LOO, and cross-validated SDEP values of 0.73, 0.61, 0.61 and 0.89, 0.64, 0.58 using the OH or the DRY probe, respectively. Additionally, the predictive performance was evaluated using an external test set of 20 compounds. Analyses of the resulting models led to the definition of a pharmacophore model that can be of interest to explain the observed affinities of known compounds as well as to design novel low molecular weight IFN inducers (IFNIs). To the best of our knowledge, this is the first 3-D QSAR application on IFN-inducing agents.

01 May 2005·Journal of Medicinal ChemistryQ1 · MEDICINE

Synthesis and Structure−Activity-Relationships of 1H-Imidazo[4,5-c]quinolines That Induce Interferon Production

Q1 · MEDICINE

Article

Author: Weeks, Charles E. ; Bastard, Yvon ; Knafla, Roy T. ; Jacobson, Joel R. ; Testerman, Tracy L. ; Oneyemi, Folakemi Y. ; Lupu, Michel ; Wagner, Tammy L. ; Pecore, Sharon E. ; Lindstrom, Kyle J. ; Parkhurst, Gwen J. ; Bomersine, Shannon N. ; Gibson, Shiela J. ; Gerster, John F. ; Miller, Richard L. ; Imbertson, Linda M. ; Reiter, Michael J. ; Maye, Peter V. ; Scribner, Lisa S. ; Thompson, Natalie J. ; Birmachu, Woubalem ; Tomai, Mark A. ; Nikolaides, Nickolas ; Andre, Jean-Denis ; Lagain, Daniel

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. Subsequently, we found that the compounds also induce in vitro production of IFN in human peripheral blood mononuclear cells (hPBMCs). The in vitro results reported herein and the in vivo results reported previously led to the discovery of imiquimod, 26, which was developed as a topical agent and has been approved for the treatment of genital warts, actinic keratosis, and superficial basal cell carcinoma.

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