Development of a novel therapeutic suppressor of brain proinflammatory cytokine up-regulation that attenuates synaptic dysfunction and behavioral deficits.
We report the development of a novel, aqueous-soluble, safe, small molecule, experimental therapeutic that suppresses injury-induced, proinflammatory cytokine increases in the brain, with resultant attenuation of synaptic protein biomarker loss and improvement in hippocampus-dependent behavioral deficits. A GMP production scheme for the active pharmaceutical ingredient, compound 17, is presented. The development and large-scale availability of this novel compound allow exploration of new, potentially disease-modifying, therapeutic approaches to CNS disorders.
Hu
Wenhui
W
Center for Drug Discovery and Chemical Biology, Northwestern University, 303 E. Chicago Avenue, Mail Code W896, Chicago, IL 60611, USA.
Ralay Ranaivo
Hantamalala
H
Roy
Saktimayee M
SM
Behanna
Heather A
HA
Wing
Laura K
LK
Munoz
Lenka
L
Guo
Ling
L
Van Eldik
Linda J
LJ
Watterson
D Martin
DM
D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects*; D001682:Biological Availability; D001923:Brain Chemistry / Q000187:drug effects*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D016207:Cytokines / Q000096:biosynthesis*; D015195:Drug Design; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D006624:Hippocampus / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D017628:Microglia / Q000187:drug effects; D018697:Nootropic Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D018697:Nootropic Agents; D011724:Pyridazines; D011743:Pyrimidines; C534736:minozac