Highly potent, orally available anti-inflammatory broad-spectrum chemokine inhibitors.
A series of 3-acylaminocaprolactams are inhibitors of chemokine-induced chemotaxis. Branching of the side chain alpha-carbon provides highly potent inhibitors of a range of CC and CXC chemokines. The most potent compound has an ED(50) of 40 pM. Selected compounds were tested in an in vivo inflammatory assay, and the best compound reduces TNF-alpha levels with an ED(50) of 0.1 microg/kg when administered by either subcutaneous injection or oral delivery.
Fox
David J
DJ
Department of Chemistry, University of Cambridge, Cambridge, UK. d.j.fox@warwick.ac.uk
Reckless
Jill
J
Lingard
Hannah
H
Warren
Stuart
S
Grainger
David J
DJ
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002209:Caprolactam / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D018925:Chemokines / Q000037:antagonists & inhibitors*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D009504:Neutrophils / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D000893:Anti-Inflammatory Agents; D018925:Chemokines; D014409:Tumor Necrosis Factor-alpha; D002209:Caprolactam