Fox D, Reckless J, Wilbert S, Greig I, Warren SG, Grainger DJ. (2005) Identification of 3-(acylamino)azepan-2-ones as stable broad-spectrum chemokine inhibitors (BSCI) resistant to metabolism, in vivo. J. Med. Chem. 48:867-874.
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.