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

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.