title: Discovery of novel phenolic antioxidants as inhibitors of vascular cell adhesion molecule-1 expression for use in chronic inflammatory diseases.
abstract: 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.
authors.affiliation: AtheroGenics, Inc., 8995 Westside Parkway, Alpharetta, Georgia 30004, USA. cmeng@atherogenics.com
authors.forename: Charles Q
authors.initials: CQ
authors.lastname: Meng
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Somers
authors.forename: Lee K
authors.initials: LK
authors.lastname: Hoong
authors.forename: X Sharon
authors.initials: XS
authors.lastname: Zheng
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Ye
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Worsencroft
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Simpson
authors.forename: Martha R
authors.initials: MR
authors.lastname: Hotema
authors.forename: M David
authors.initials: MD
authors.lastname: Weingarten
authors.forename: Mathew L
authors.initials: ML
authors.lastname: MacDOnald
authors.forename: Russell R
authors.initials: RR
authors.lastname: Hill
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Marino
authors.forename: Ki-Ling
authors.initials: KL
authors.lastname: Suen
authors.forename: Jayraz
authors.initials: J
authors.lastname: Luchoomun
authors.forename: Charles
authors.initials: C
authors.lastname: Kunsch
authors.forename: Laura K
authors.initials: LK
authors.lastname: Landers
authors.forename: Dimitria
authors.initials: D
authors.lastname: Stefanopoulos
authors.forename: Randy B
authors.initials: RB
authors.lastname: Howard
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Sundell
authors.forename: Uday
authors.initials: U
authors.lastname: Saxena
authors.forename: Martin A
authors.initials: MA
authors.lastname: Wasserman
authors.forename: James A
authors.initials: JA
authors.lastname: Sikorski
mesh_terms: 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
chemical_list: 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