Design, synthesis, and preliminary pharmacological evaluation of N-acyl-3-aminoglutarimides as broad-spectrum chemokine inhibitors in vitro and anti-inflammatory agents in vivo.
A series of N-substituted 3-aminoglutarimides have been synthesized and tested for inhibitory activity against a range of chemokines in vitro and for suppression of lipopolysaccharide-induced inflammation in vivo. The results show that they represent the first class of small molecules with broad-spectrum chemokine inhibitory effects. Among the compounds studied, 10 (NR58,4) was the most potent, being active at doses between 5 and 15 nM in vitro and at 0.3 mg kg(-1) in vivo.
Fox
David J
DJ
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
Reckless
Jill
J
Warren
Stuart G
SG
Grainger
David J
DJ
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018932:Chemokine CCL2 / Q000737:chemistry* / Q000494:pharmacology; D018925:Chemokines / Q000037:antagonists & inhibitors*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D010881:Piperidones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C446054:3-(undec-10-enoylamino)glutarimide; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018932:Chemokine CCL2; D018925:Chemokines; D008070:Lipopolysaccharides; D009842:Oligopeptides; D010446:Peptide Fragments; D010881:Piperidones; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha