211242-52-3Relevant articles and documents
Discovery of 3,5-Diphenyl-4-methyl-1,3-oxazolidin-2-ones as Novel, Potent, and Orally Available Δ-5 Desaturase (D5D) Inhibitors
Fujimoto, Jun,Okamoto, Rei,Noguchi, Naoyoshi,Hara, Ryoma,Masada, Shinichi,Kawamoto, Tetsuji,Nagase, Hiroki,Tamura, Yumiko Okano,Imanishi, Mitsuaki,Takagahara, Shuichi,Kubo, Kazuki,Tohyama, Kimio,Iida, Koichi,Andou, Tomohiro,Miyahisa, Ikuo,Matsui, Junji,Hayashi, Ryouta,Maekawa, Tsuyoshi,Matsunaga, Nobuyuki
, p. 8963 - 8981 (2017/11/14)
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.
