Identification of 3-(acylamino)azepan-2-ones as stable broad-spectrum chemokine inhibitors resistant to metabolism in vivo.
3-(acylamino)glutarimides, a class of broad spectrum chemokine inhibitors, are rapidly hydrolyzed in serum, despite being stable in aqueous solution. Synthesis and high-performance liquid chromatography analysis of the proposed N-acyl-glutamate and -glutamine metabolites establish the enzyme-catalyzed breakdown pathways. In vitro assays suggest that despite their short half-life in vivo, the parent acylamino-glutarimides, not the ring-opened hydrolysis products, are the source of the antiinflammatory activity. Identification of this metabolic pathway has led to the development of 3-(acylamino)azepan-2-ones that are also broad spectrum chemokine inhibitors and act as stable, orally available powerful antiinflammatory agents in vivo with doses of 1 mg/kg.
Fox
David J
DJ
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK. djf34@cam.ac.uk
Reckless
Jill
J
Wilbert
Sibylle M
SM
Greig
Ian
I
Warren
Stuart
S
Grainger
David J
DJ
D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001381:Azepines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D018925:Chemokines / Q000037:antagonists & inhibitors*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D007279:Injections, Subcutaneous; D007769:Lactams / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D010881:Piperidones / Q000493:pharmacokinetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation
D000893:Anti-Inflammatory Agents; D001381:Azepines; D018925:Chemokines; D007769:Lactams; D010881:Piperidones; D014409:Tumor Necrosis Factor-alpha; C007864:glutarimide