Discovery of Novel Benzoxazinones as Potent and Orally Active Long Chain Fatty Acid Elongase 6 Inhibitors
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- 作者：Takashi Mizutani ; Shiho Ishikawa ; Tsuyoshi Nagase ; Hidekazu Takahashi ; Takashi Fujimura ; Takahide Sasaki ; Akira Nagumo ; Ken Shimamura ; Yasuhisa Miyamoto ; Hidefumi Kitazawa ; Maki Kanesaka ; Ryo Yoshimot
- 刊名：Journal of Medicinal Chemistry
- 出版年：2009
- 出版时间：November 26, 2009
- 年：2009
- 卷：52
- 期：22
- 页码：7289-7300
- 全文大小：885K
- 年卷期：v.52,no.22(November 26, 2009)
- ISSN：1520-4804
文摘
A series of benzoxazinones was synthesized and evaluated as novel long chain fatty acid elongase 6 (ELOVL6) inhibitors. Exploration of the SAR of the UHTS lead 1a led to the identification of (S)-1y that possesses a unique chiral quarternary center and a pyrazole ring as critical pharmacophore elements. Compound (S)-1y showed potent and selective inhibitory activity toward human ELOVL6 while displaying potent inhibitory activity toward both mouse ELOVL3 and 6 enzymes. Compound (S)-1y showed acceptable pharmacokinetic profiles after oral dosing in mice. Furthermore, (S)-1y significantly suppressed the elongation of target fatty acids in mouse liver at 30 mg/kg oral dosing.