Design, synthesis and biological evaluation of γ-lactam hydroxamate based TACE inhibitors

Abstract

A new series of γ-lactam hydroxamate based TACE inhibitors was designed mainly by introducing various substitutions at the 2nd position of the quinoline nucleus to achieve high potency and good selectivity towards TACE over matrix metalloproteases (MMPs) and ADAM-10. In ex vivo TNF-α inhibitory activity assays, compounds 11o and 11p were identified as the most potent compounds. The in vitro TACE inhibitory activity, selectivity over MMPs and ADAM-10 and the in vivo TNF-α inhibitory activities of compounds 11o and 11p were assessed and lead compound 11p was identified. Preliminary toxicity and pharmacokinetic (PK) studies were conducted for compound 11p and it showed an improved PK and clean toxicological profile compared to standard compound 1. Altogether, these results demonstrated the discovery of highly potent and selective γ-lactam hydroxamate based TACE inhibitors which show potential for the safe and effective treatment of inflammatory diseases.