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.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Antioxidants/chemical synthesis , Phenols/chemical synthesis , Sulfides/chemical synthesis , Vascular Cell Adhesion Molecule-1/biosynthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anticholesteremic Agents/chemical synthesis , Anticholesteremic Agents/chemistry , Anticholesteremic Agents/pharmacology , Antioxidants/chemistry , Antioxidants/pharmacology , Cells, Cultured , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Chronic Disease , Cricetinae , Depression, Chemical , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Humans , Inflammation/drug therapy , Interleukin-1/antagonists & inhibitors , Interleukin-1/metabolism , Interleukin-6/antagonists & inhibitors , Interleukin-6/metabolism , Male , Mice , Mice, Inbred BALB C , Phenols/chemistry , Phenols/pharmacology , Probucol/chemistry , Structure-Activity Relationship , Sulfides/chemistry , Sulfides/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Novel chalcone derivatives have been discovered as potent inhibitors of TNF-alpha-induced VCAM-1 expression. Thienyl or benzothienyl substitution at the meta-position of ring B helps boost potency while large substitution at the para-position on ring B is detrimental. Various substitutions are tolerated on ring A. A lipophilicity-potency relationship has been observed in several sub-series of compounds.
Subject(s)
Chalcone/chemistry , Chalcone/pharmacology , Tumor Necrosis Factor-alpha/pharmacology , Vascular Cell Adhesion Molecule-1/biosynthesis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
alpha,beta-Unsaturated sulfones have been discovered from a combinatorial library as leads for a new series of inhibitors of inducible VCAM-1 expression. Although not essential, further conjugation of the sulfonyl group to another vinyl group or a phenyl group increases the potency dramatically.
Subject(s)
Combinatorial Chemistry Techniques , Sulfones/chemistry , Sulfones/pharmacology , Vascular Cell Adhesion Molecule-1/drug effects , Cells, Cultured , Gene Expression Regulation/drug effects , Humans , Inhibitory Concentration 50 , Structure-Activity Relationship , Vascular Cell Adhesion Molecule-1/biosynthesisABSTRACT
A series of novel phenolic compounds has been discovered as potent inhibitors of TNF-alpha-inducible expression of vascular cell adhesion molecule-1 (VCAM-1) with concurrent antioxidant and lipid-modulating properties. Optimization of these multifunctional agents led to the identification of 3a (AGI-1067) as a clinical candidate with demonstrated efficacies in animal models of atherosclerosis and hyperlipidemia.
