Journal of Medicinal Chemistry 2005-02-10

Identification of 3-(acylamino)azepan-2-ones as stable broad-spectrum chemokine inhibitors resistant to metabolism in vivo.

David J Fox, Jill Reckless, Sibylle M Wilbert, Ian Greig, Stuart Warren, David J Grainger

Index: J. Med. Chem. 48 , 867-74, (2005)

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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.