PMID- 12626663
OWN - NLM
STAT- MEDLINE
DCOM- 20030707
LR  - 20220310
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 305
IP  - 3
DP  - 2003 Jun
TI  - AGI-1067: a multifunctional phenolic antioxidant, lipid modulator, 
      anti-inflammatory and antiatherosclerotic agent.
PG  - 1116-23
AB  - To explore the therapeutic efficacy and potential mechanisms of action of a new 
      class of antiatherosclerotic drugs, AGI-1067 
      [mono[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenyl] 
      ester] (butanedioc acid) was tested in several animal models of atherosclerosis. 
      AGI-1067, a novel phenolic antioxidant, was well tolerated in a 1-year study in 
      hypercholesterolemic cynomolgus monkeys. It lowered low-density lipoprotein 
      cholesterol (LDLc) by 41 and 90% at oral doses of 50 and 150 mg/kg, respectively 
      and increased high-density lipoprotein cholesterol (HDLc) by 107% at the higher 
      dose. In contrast, another phenolic antioxidant, probucol, had a modest 
      LDLc-lowering effect (15% at 250 mg/kg) while decreasing HDLc (37% at 150 mg/kg). 
      Histopathology of the aortas and coronary arteries revealed no atherosclerosis in 
      the AGI-1067 (150 mg/kg) group and minimal-to-moderate atherosclerosis in the 
      vehicle and probucol (150 mg/kg) groups. AGI-1067 also inhibited atherosclerosis 
      in LDL receptor-deficient (LDLr -/-) mice and apolipoprotein E-deficient (ApoE 
      -/-) mice even in the absence of a lipid-lowering effect. In LDLr -/- mice, 
      AGI-1067 reduced aortic atherosclerosis by 49%. In ApoE -/- mice, AGI-1067 
      reduced atherosclerosis by 25, 41, and 49% in the arch, thoracic, and abdominal 
      regions of the aorta. AGI-1067 also reduced vascular cell adhesion molecule-1 
      (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) mRNA levels in lungs of 
      lipopolysaccharide-stimulated mice. At the cellular level, AGI-1067 inhibited 
      tumor necrosis factor-alpha-inducible expression of VCAM-1, MCP-1, and E-selectin 
      in human aortic endothelial cells (IC50 values = 6, 10, and 25 microM, 
      respectively). These data show that AGI-1067 can inhibit atherosclerosis not only 
      via its lipid-lowering effects but also by having direct anti-inflammatory 
      effects on the vessel wall and suggest that it may be a novel therapeutic agent 
      for coronary artery disease.
FAU - Sundell, Cynthia L
AU  - Sundell CL
AD  - Discovery Research, AtheroGenics, Inc., 8995 Westside Parkway, Alpharetta, GA 
      30004, USA. csundell@atherogenics.com
FAU - Somers, Patricia K
AU  - Somers PK
FAU - Meng, Charles Q
AU  - Meng CQ
FAU - Hoong, Lee K
AU  - Hoong LK
FAU - Suen, Ki-Ling
AU  - Suen KL
FAU - Hill, Russell R
AU  - Hill RR
FAU - Landers, Laura K
AU  - Landers LK
FAU - Chapman, Angela
AU  - Chapman A
FAU - Butteiger, Dustie
AU  - Butteiger D
FAU - Jones, Moira
AU  - Jones M
FAU - Edwards, David
AU  - Edwards D
FAU - Daugherty, Alan
AU  - Daugherty A
FAU - Wasserman, Martin A
AU  - Wasserman MA
FAU - Alexander, R Wayne
AU  - Alexander RW
FAU - Medford, Russell M
AU  - Medford RM
FAU - Saxena, Uday
AU  - Saxena U
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20030306
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Anticholesteremic Agents)
RN  - 0 (Antioxidants)
RN  - J1J54V24R4 (succinobucol)
RN  - P3CTH044XJ (Probucol)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents/*pharmacology
MH  - Anticholesteremic Agents/*pharmacology
MH  - Antioxidants/*pharmacology
MH  - Arteriosclerosis/prevention & control
MH  - Disease Models, Animal
MH  - Endothelium, Vascular/drug effects/metabolism
MH  - Humans
MH  - *Lipid Metabolism
MH  - Macaca fascicularis
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Oxidation-Reduction/drug effects
MH  - Probucol/analogs & derivatives/*pharmacology
EDAT- 2003/03/11 04:00
MHDA- 2003/07/08 05:00
CRDT- 2003/03/11 04:00
PHST- 2003/03/11 04:00 [pubmed]
PHST- 2003/07/08 05:00 [medline]
PHST- 2003/03/11 04:00 [entrez]
AID - jpet.102.048132 [pii]
AID - 10.1124/jpet.102.048132 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2003 Jun;305(3):1116-23. doi: 10.1124/jpet.102.048132. Epub 
      2003 Mar 6.