Discovery of new chemical classes of synthetic ligands that suppress neuroinflammatory responses.
We used a chemical genomics approach that includes follow up in parallel syntheses to discover a new class of compounds that selectively suppress glial activation. While the mechanism of action remains to be determined, available data and the experimental approach for discovery indicate that the mechanism includes inhibition of gene regulating protein kinases. Specifically, the increased production of IL-1beta and iNOS in response to various activating stimuli, including Abeta1-42, is suppressed while the production of potentially beneficial responses, such as ApoE production, is not inhibited. The increased production of COX-2 and p38 MAPK activation are also not altered, demonstrating the novel nature of potential therapeutic targets compared to currently available drugs. The chemical scaffold is 3-aminopyridazine (3-AP). This is an attractive scaffold because of its potential for diversification by established, facile chemistries and the prior use of a 3-AP scaffold in other central nervous system targeted therapeutics. Therefore, the potential bioavailability of 3-AP derivatives and the demonstrated cellular selectivity demand that future research address the potential efficacy of selective 3-AP derivatives in animal models of disease.
Watterson
D Martin
DM
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago IL 60611-3008, USA. m-watterson@northwestern.edu
Haiech
Jacques
J
Van Eldik
Linda J
LJ
D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy; D007375:Interleukin-1 / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases
D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001057:Apolipoproteins E; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D007527:Isoenzymes; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; C075222:amyloid beta-protein (1-42); D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases