Discovery and structure-activity relationships of 6-(benzoylamino)benzoxaboroles as orally active anti-inflammatory agents.
Structure-activity relationships of 6-(benzoylamino)benzoxaborole analogs were investigated for the inhibition of TNF-α, IL-1β, and IL-6 from lipopolysaccharide stimulated peripheral blood mononuclear cells. Compound 1q showed potent activity against all three cytokines with IC50 values between 0.19 and 0.50μM, inhibited LPS-induced TNF-α and IL-6 elevation in mice and improved collagen-induced arthritis in mice. Compound 1q (AN4161) is considered to be a promising lead for novel anti-inflammatory agent with an excellent pharmacokinetic profile.
Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA. Electronic address: takama@anacor.com.
Tsutomu
T
Akama
Chen
C
Dong
Charlotte
C
Virtucio
Yvonne R
YR
Freund
Daitao
D
Chen
Matthew D
MD
Orr
Robert T
RT
Jacobs
Yong-Kang
YK
Zhang
Vincent
V
Hernandez
Yang
Y
Liu
Anne
A
Wu
Wei
W
Bu
Liang
L
Liu
Kurt
K
Jarnagin
Jacob J
JJ
Plattner
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001555:Benzene Derivatives / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001896:Boron Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D053583:Interleukin-1beta / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D000893:Anti-Inflammatory Agents; D001555:Benzene Derivatives; D001896:Boron Compounds; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha
Anti-inflammatory; Benzoxaborole; Collagen-induced arthritis; Cytokine; Interleukin-1beta; Interleukin-6; Pharmacokinetics; Structure–activity relationships; Tumor necrosis factor-alpha