Journal of Medicinal Chemistry p. 8963 - 8981 (2017)
Update date:2022-08-15
Topics:
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
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.
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