title: Synthesis and structure-activity-relationships of 1H-imidazo[4,5-c]quinolines that induce interferon production.
abstract: 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.
authors.affiliation: 3M Pharmaceuticals, 3M Center, Building 270-4S-02, St. Paul, Minnesota 55144-1000, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Gerster
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Lindstrom
authors.forename: Richard L
authors.initials: RL
authors.lastname: Miller
authors.forename: Mark A
authors.initials: MA
authors.lastname: Tomai
authors.forename: Woubalem
authors.initials: W
authors.lastname: Birmachu
authors.forename: Shannon N
authors.initials: SN
authors.lastname: Bomersine
authors.forename: Shiela J
authors.initials: SJ
authors.lastname: Gibson
authors.forename: Linda M
authors.initials: LM
authors.lastname: Imbertson
authors.forename: Joel R
authors.initials: JR
authors.lastname: Jacobson
authors.forename: Roy T
authors.initials: RT
authors.lastname: Knafla
authors.forename: Peter V
authors.initials: PV
authors.lastname: Maye
authors.forename: Nickolas
authors.initials: N
authors.lastname: Nikolaides
authors.forename: Folakemi Y
authors.initials: FY
authors.lastname: Oneyemi
authors.forename: Gwen J
authors.initials: GJ
authors.lastname: Parkhurst
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Pecore
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Reiter
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Scribner
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Testerman
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Thompson
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Wagner
authors.forename: Charles E
authors.initials: CE
authors.lastname: Weeks
authors.forename: Jean-Denis
authors.initials: JD
authors.lastname: Andre
authors.forename: Daniel
authors.initials: D
authors.lastname: Lagain
authors.forename: Yvon
authors.initials: Y
authors.lastname: Bastard
authors.forename: Michel
authors.initials: M
authors.lastname: Lupu
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D006168:Guinea Pigs; D018258:Herpesvirus 2, Human / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000077271:Imiquimod; D007369:Interferon Inducers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007372:Interferons / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000634:Aminoquinolines; D000998:Antiviral Agents; D007093:Imidazoles; D007369:Interferon Inducers; D011804:Quinolines; D007372:Interferons; D000077271:Imiquimod