Discovery of 3,5-Diphenyl-4-methyl-1,3-oxazolidin-2-ones as Novel, Potent, and Orally Available Δ-5 Desaturase (D5D) Inhibitors
| Autor: | Mitsuaki Imanishi, Shinichi Masada, Ikuo Miyahisa, Kimio Tohyama, Shuichi Takagahara, Tomohiro Andou, Tetsuji Kawamoto, Hiroki Nagase, Ryouta Hayashi, Jun Fujimoto, Rei Okamoto, Nobuyuki Matsunaga, Kazuki Kubo, Koichi Iida, Naoyoshi Noguchi, Yumiko Okano Tamura, Tsuyoshi Maekawa, Ryoma Hara, Junji Matsui |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Fatty Acid Desaturases
Intrinsic activity Stereochemistry Substituent Administration Oral Biological Availability 010402 general chemistry 01 natural sciences chemistry.chemical_compound Mice Structure-Activity Relationship Delta-5 Fatty Acid Desaturase In vivo Drug Discovery Moiety Animals Oxazolidinones Arachidonic Acid 010405 organic chemistry Chemistry Atherosclerosis In vitro 0104 chemical sciences Bioavailability Liver Molecular Medicine Arachidonic acid Pharmacophore |
| Zdroj: | Journal of medicinal chemistry. 60(21) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|