Aortic Binding of AZD5248: Mechanistic Insight and Reactivity Assays To Support Lead Optimzation

Chemical Research in Toxicology
Ryan A BraggJonathan Tugwood

Abstract

The oral dipeptidyl peptidase 1 (DPP1) inhibitor AZD5248 showed aortic binding in a rat quantitative whole-body autoradiography (QWBA) study, and its development was terminated prior to human dosing. A mechanistic hypothesis for this finding was established invoking reactivity with aldehydes involved in the cross-linking of elastin, a major component of aortic tissue. This was tested by developing a simple aldehyde chemical reactivity assay and a novel in vitro competitive covalent binding assay. Results obtained with AZD5248, literature compounds, and close analogues of AZD5248 support the mechanistic hypothesis and provide validation for the use of these assays in a two tier screening approach to support lead optimization. The strengths and limitations of these assays are discussed.

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Citations

Mar 23, 2017·Journal of Labelled Compounds & Radiopharmaceuticals·Lee KingstonCharles S Elmore
Dec 17, 2020·Journal of Labelled Compounds & Radiopharmaceuticals·Lee KingstonCharles S Elmore
Oct 23, 2020·Scientific Reports·Raphael ReinboldRichard J Hopkinson
May 31, 2019·Journal of Medicinal Chemistry·Weijie HouZhiyuan Zhang

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