Discovery of novel phenolic antioxidants as inhibitors of vascular cell adhesion molecule-1 expression for use in chronic inflammatory diseases.
Vascular cell adhesion molecule-1 (VCAM-1) mediates recruitment of leukocytes to endothelial cells and is implicated in many inflammatory conditions. Since part of the signal transduction pathway that regulates the activation of VCAM-1 expression is redox-sensitive, compounds with antioxidant properties may have inhibitory effects on VCAM-1 expression. Novel phenolic compounds have been designed and synthesized starting from probucol (1). Many of these compounds demonstrated potent inhibitory effects on cytokine-induced VCAM-1 expression and displayed potent antioxidant effects in vitro. Some of these derivatives (4o, 4p, 4w, and 4x) inhibited lipopolysaccharide (LPS)-induced secretion of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and IL-6 from human peripheral blood mononuclear cells (hPBMCs) in a concentration-dependent manner in vitro and showed antiinflammatory effects in an animal model. Compounds 4ad and 4ae are currently in clinical trials for the treatment of rheumatoid arthritis (RA) and prevention of chronic organ transplant rejection, respectively.
Meng
Charles Q
CQ
AtheroGenics, Inc., 8995 Westside Parkway, Alpharetta, Georgia 30004, USA. cmeng@atherogenics.com
Somers
Patricia K
PK
Hoong
Lee K
LK
Zheng
X Sharon
XS
Ye
Zhihong
Z
Worsencroft
Kimberly J
KJ
Simpson
Jacob E
JE
Hotema
Martha R
MR
Weingarten
M David
MD
MacDOnald
Mathew L
ML
Hill
Russell R
RR
Marino
Elaine M
EM
Suen
Ki-Ling
KL
Luchoomun
Jayraz
J
Kunsch
Charles
C
Landers
Laura K
LK
Stefanopoulos
Dimitria
D
Howard
Randy B
RB
Sundell
Cynthia L
CL
Saxena
Uday
U
Wasserman
Martin A
MA
Sikorski
James A
JA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000975:Antioxidants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D002908:Chronic Disease; D006224:Cricetinae; D003864:Depression, Chemical; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011341:Probucol / Q000737:chemistry / Q000031:analogs & derivatives; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis*; D000093242:Interleukin-6 Inhibitors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000924:Anticholesteremic Agents; D000975:Antioxidants; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D007375:Interleukin-1; D015850:Interleukin-6; D010636:Phenols; D011341:Probucol; D013440:Sulfides; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D000093242:Interleukin-6 Inhibitors; C494726:4-(4-((1-((3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)thio)-1-methylethyl)thio)-2,6-bis(1,1-dimethylethyl)phenoxy)butanoic acid; C494725:camobucol