Identification of a novel boronic acid as a potent, selective, and orally active hormone sensitive lipase inhibitor

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• 作者：Tomoko Ogiyama^a ; ^{yamamoto.tomoko.me@daiichisankyo.co.jp" class="auth_mail" title="E-mail the corresponding author} ; Mitsuhiro Yamaguchi^a ; Nobuya Kurikawa^a ; Shoko Honzumi^a ; Yuka Yamamoto^b ; Daisuke Sugiyama^a ; Shinichi Inoue^a
• 关键词：Hormone sensitive lipase (HSL) ; Dyslipidemia ; Lipolysis ; Boronic acid
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 August 2016
• 年：2016
• 卷：24
• 期：16
• 页码：3801-3807
• 全文大小：1179 K

文摘

Hormone sensitive lipase (HSL) is an attractive therapeutic target of dyslipidemia. We designed and synthesized several compounds as reversible HSL inhibitors with a focus on hydrophobic interactions, which was thought to be effective upon the HSL inhibitory activity. In these efforts, we identified boronated compound 12 showing a potent HSL inhibitory activity with an IC₅₀ value of 7 nM and a high selectivity against cholinesterases. Furthermore, compound 12 is the first boron containing HSL inhibitor that has shown an antilipolytic effect in rats after oral administration at 3 mg/kg.