Why the study?
The oral DPP1 inhibitor AZD5248 showed aortic binding in a rat QWBA study, prompting investigation of the underlying mechanism to support lead optimization.
Answers are grounded in this paper and cite their sources.
May warrant safety screening in DPP-1 inhibitor trials for bronchiectasis; leaves open optimized development via aldehyde reactivity assays.
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.
No takes yet. Share an insight, caveat, or question.
Bragg et al. (2015) conducted a review in Bronchiectasis. DPP-1 inhibitors was evaluated.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: