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

  • Bioorg Med Chem. 2016 Aug 15;24(16):3801-7. doi: 10.1016/j.bmc.2016.06.022.
Tomoko Ogiyama  1 ,  Mitsuhiro Yamaguchi  2 ,  Nobuya Kurikawa  2 ,  Shoko Honzumi  2 ,  Yuka Yamamoto  3 ,  Daisuke Sugiyama  2 ,  Shinichi Inoue  2
Affiliations
  • 1. R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: [email protected].
  • 2. R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 3. Daiichi Sankyo RD Novare Co., Ltd., 1-16-13, Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan.
PMID: 27338659 DOI: 10.1016/j.bmc.2016.06.022
Abstract

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 7nM 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 3mg/kg.

Keywords
Boronic acid; Dyslipidemia; Hormone sensitive lipase (HSL); Lipolysis.