Design of Benzoxathiazin-3-one 1,1-Dioxides as a New Class of Irreversible Serine Hydrolase Inhibitors: Discovery of a Uniquely Selective PNPLA4 Inhibitor

Journal of the American Chemical Society
Anne F KornahrensD L Boger

Abstract

The design and examination of 4,1,2-benzoxathiazin-3-one 1,1-dioxides as candidate serine hydrolase inhibitors are disclosed, and represent the synthesis and study of a previously unexplored heterocycle. This new class of activated cyclic carbamates provided selective irreversible inhibition of a small subset of serine hydrolases without release of a leaving group, does not covalently modify active site catalytic cysteine and lysine residues of other enzyme classes, and was found to be amenable to predictable structural modifications that modulate intrinsic reactivity or active site recognition. Even more remarkable and within the small pilot series of candidate inhibitors examined in an initial study, an exquisitely selective inhibitor for a poorly characterized serine hydrolase (PNPLA4, patatin-like phospholipase domain-containing protein 4) involved in adipocyte triglyceride homeostasis was discovered.

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Citations

Feb 13, 2019·Organic & Biomolecular Chemistry·Nikhil R TaskerPeter Wipf
Apr 11, 2019·Chembiochem : a European Journal of Chemical Biology·Chao WangAlexander Adibekian
Jan 26, 2021·Chembiochem : a European Journal of Chemical Biology·Jason K DutraChristopher W Am Ende
Jul 30, 2020·Cell Chemical Biology·Franco FaucherScott Lovell
Jun 5, 2021·RSC Medicinal Chemistry·Paul J KoovitsLuiz C Dias
Mar 21, 2020·ACS Chemical Biology·Stefan G KathmanBenjamin F Cravatt
Nov 21, 2021·Nature Metabolism·Gernot F GrabnerRudolf Zechner

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