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

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posted on 12.10.2017, 00:00 by Jun Fujimoto, Rei Okamoto, Naoyoshi Noguchi, Ryoma Hara, Shinichi Masada, Tetsuji Kawamoto, Hiroki Nagase, Yumiko Okano Tamura, Mitsuaki Imanishi, Shuichi Takagahara, Kazuki Kubo, Kimio Tohyama, Koichi Iida, Tomohiro Andou, Ikuo Miyahisa, Junji Matsui, Ryouta Hayashi, Tsuyoshi Maekawa, Nobuyuki Matsunaga
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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