Discovery of 3,5-Diphenyl-4-methyl-1,3-oxazolidin-2-ones as Novel, Potent, and Orally Available Δ‑5 Desaturase (D5D) Inhibitors

The
discovery and optimization of Δ-5 desaturase (D5D) inhibitors
are described. Investigation of the 1,3-oxazolidin-2-one scaffold
was inspired by a pharmacophore model constructed from the common
features of several hit compounds, resulting in the identification
of 3,5-diphenyl-1,3-oxazolidin-2-one 5h as a novel lead
showing potent in vitro activity. Subsequent optimization focused
on the modification of two metabolic sites, which provided (4S,5S)-5i, a derivative with improved metabolic
stability. Moreover, adding a substituent into the upper phenyl moiety
further enhanced the intrinsic activity, which led to the discovery
of 5-[(4S,5S)-5-(4fluorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]­benzene-1,3-dicarbonitrile (4S,5S)-5n, endowed with excellent D5D binding
affinity, cellular activity, and high oral bioavailability in a mouse.
It exhibited robust in vivo hepatic arachidonic acid/dihomo-γ-linolenic
acid ratio reduction (a target engagement marker) in an atherosclerosis
mouse model. Finally, an asymmetric synthetic procedure for this compound
was established.