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. 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.
Gerster
John F
JF
3M Pharmaceuticals, 3M Center, Building 270-4S-02, St. Paul, Minnesota 55144-1000, USA.
Lindstrom
Kyle J
KJ
Miller
Richard L
RL
Tomai
Mark A
MA
Birmachu
Woubalem
W
Bomersine
Shannon N
SN
Gibson
Shiela J
SJ
Imbertson
Linda M
LM
Jacobson
Joel R
JR
Knafla
Roy T
RT
Maye
Peter V
PV
Nikolaides
Nickolas
N
Oneyemi
Folakemi Y
FY
Parkhurst
Gwen J
GJ
Pecore
Sharon E
SE
Reiter
Michael J
MJ
Scribner
Lisa S
LS
Testerman
Tracy L
TL
Thompson
Natalie J
NJ
Wagner
Tammy L
TL
Weeks
Charles E
CE
Andre
Jean-Denis
JD
Lagain
Daniel
D
Bastard
Yvon
Y
Lupu
Michel
M
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
D000634:Aminoquinolines; D000998:Antiviral Agents; D007093:Imidazoles; D007369:Interferon Inducers; D011804:Quinolines; D007372:Interferons; D000077271:Imiquimod