Novel Piperazino-Enaminones Suppress Pro-Inflammatory Cytokines and Inhibit Chemokine Receptor CCR2.
Pro-inflammatory mediators including TNF-alpha, IL-6, and nitric oxide are important for the regulation of the immune response when an infection is present, but when overproduced, it can be responsible for the development of tissue and organ injury seen in sepsis, as well as severe asthma, and autoimmune diseases such as Crohn's disease and rheumatoid arthritis. Data from our lab to characterize the novel compound enaminone E121 have suggested that macrophages stimulated with lipopolysaccharide (LPS) release significantly decreased levels of TNF-alpha and IL-6 as measured by enzyme-linked immunosorbent assay as compared to the DMSO control group. Additionally, functional experiments in a mouse model of asthma have shown that E121 is efficacious in decreasing airway hyperresponsiveness. A new set of compounds synthesized in our lab (JODI) have an N-aryl piperazino motif incorporated on the aromatic side of the enaminone pharmacophore. It was hypothesized that this would enhance their immunosuppressive activity as anti-inflammatory agents by also acting as a chemokine receptor antagonist. Our studies suggest that JODI appears to suppress TNF-alpha and IL-6 in a dose-dependent manner. The JODI compounds were also more effective in reducing TNF-alpha after LPS stimulation when compared to dexamethasone. Lastly, studies using MCP-1 suggest that the JODI compounds, and not E121, are able to block CCR2 signaling as evidenced by decreased total ERK1/2. These studies indicate that E121 and its corresponding piperazino analogs could act as strong anti-inflammatory agents in asthma or other autoimmunities where efficacious therapeutic options are needed.
Department of Pharmaceutical Sciences, University of Saint Joseph School of Pharmacy, 229 Trumbull Street, Hartford, CT, 06103, USA. dszollosi@usj.edu.
Doreen E
DE
Szollosi
Department of Pharmaceutical Sciences, University of Saint Joseph School of Pharmacy, 229 Trumbull Street, Hartford, CT, 06103, USA.
Ola A M
OA
Ghoneim
Department of Pharmaceutical Sciences, University of Saint Joseph School of Pharmacy, 229 Trumbull Street, Hartford, CT, 06103, USA.
Mohammed K
MK
Manzoor
Department of Pharmacology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555, USA.
Jyothi
J
Dhuguru
Department of Pharmaceutical Sciences, University of Saint Joseph School of Pharmacy, 229 Trumbull Street, Hartford, CT, 06103, USA.
Ivan O
IO
Edafiogho
D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D016207:Cytokines / Q000187:drug effects*; D051379:Mice; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors; D019707:Receptors, Chemokine / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects; D000093242:Interleukin-6 Inhibitors
D000814:Aniline Compounds; D000893:Anti-Inflammatory Agents; D003509:Cyclohexanecarboxylic Acids; D016207:Cytokines; D010879:Piperazines; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C483746:E 121 compound
asthma; autoimmunity; chemokines; inflammation; macrophages; piperazino-enaminones; pro-inflammatory cytokines