新型激素敏感脂肪酶抑制剂系列的设计、合成及药理评价
Design, synthesis, and pharmacological evaluation of a novel series of hormone sensitive lipase inhibitor.
作者信息
Ogiyama Tomoko, Yamaguchi Mitsuhiro, Kurikawa Nobuya, Honzumi Shoko, Terayama Koji, Nagaoka Nobumi, Yamamoto Yuka, Kimura Takako, Sugiyama Daisuke, Inoue Shin-Ichi
机构信息
Modality Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
R&D Planning & Management Department, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
出版信息
Bioorg Med Chem. 2017 Sep 1;25(17):4817-4828. doi: 10.1016/j.bmc.2017.07.028. Epub 2017 Jul 17.
HSL inhibition is a promising approach to the treatment of dyslipidemia. As a result of re-optimization of lead compound 2, we identified novel compound 25a exhibiting potent inhibitory activity against HSL enzyme and cell with high selectivity for cholinesterases (AChE and BuChE). Reflecting its potent in vitro activity, compound 25a exhibited antilipolytic effect in rats at 1mg/kg p.o., which indicated that this novel compound is the most potent orally active HSL inhibitor. Moreover, compound 25a did not show bioactivation liability.
抑制激素敏感脂肪酶（HSL）是一种很有前景的治疗血脂异常的方法。通过对先导化合物2进行重新优化，我们鉴定出了新型化合物25a，它对HSL酶具有强效抑制活性，并且对胆碱酯酶（乙酰胆碱酯酶和丁酰胆碱酯酶）具有高选择性。鉴于其强大的体外活性，化合物25a在大鼠口服剂量为1mg/kg时表现出抗脂解作用，这表明这种新型化合物是最有效的口服活性HSL抑制剂。此外，化合物25a没有显示出生物活化风险。
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