title: Identification of 3-(acylamino)azepan-2-ones as stable broad-spectrum chemokine inhibitors resistant to metabolism in vivo.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK. djf34@cam.ac.uk
authors.forename: David J
authors.initials: DJ
authors.lastname: Fox
authors.forename: Jill
authors.initials: J
authors.lastname: Reckless
authors.forename: Sibylle M
authors.initials: SM
authors.lastname: Wilbert
authors.forename: Ian
authors.initials: I
authors.lastname: Greig
authors.forename: Stuart
authors.initials: S
authors.lastname: Warren
authors.forename: David J
authors.initials: DJ
authors.lastname: Grainger
mesh_terms: 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
chemical_list: D000893:Anti-Inflammatory Agents; D001381:Azepines; D018925:Chemokines; D007769:Lactams; D010881:Piperidones; D014409:Tumor Necrosis Factor-alpha; C007864:glutarimide