2. Academic Validation
  3. Identification of a novel hormone sensitive lipase inhibitor with a reduced potential of reactive metabolites formation

Identification of a novel hormone sensitive lipase inhibitor with a reduced potential of reactive metabolites formation

  • Bioorg Med Chem. 2017 Apr 1;25(7):2234-2243. doi: 10.1016/j.bmc.2017.02.045.
Tomoko Ogiyama 1,  Mitsuhiro Yamaguchi 2,  Nobuya Kurikawa 3,  Shoko Honzumi 4,  Yuka Yamamoto 5,  Daisuke Sugiyama 6,  Hideo Takakusa 6,  Shin-Ichi Inoue 6
Affiliations

Affiliations

  • 1 Modality Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: [email protected].
  • 2 R&D Planning & Management Department, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 3 Venture Science Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 4 Rare Disease & LCM Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 5 Biological Research Department, Daiichi Sankyo RD Novare Co., Ltd., 1-16-13, Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
  • 6 Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
PMID: 28279560 DOI: 10.1016/j.bmc.2017.02.045
Abstract

Hormone sensitive Lipase (HSL) has emerged as an attractive target for the treatment of dyslipidemia. We previously reported compound 1 as a potent and orally active HSL inhibitor. Although an attractive profile was demonstrated, subsequent studies revealed that compound 1 has a bioactivation liability. The oxygen-carbon linker in compound 1 was identified as being potentially responsible for reactive metabolite formation. By exchanging of this susceptible fragment was feasible, and a benzanilide derivative 6b with a decreased bioactivation liability was obtained. Further modification of the novel benzanilide scaffold resulted in the identification of compound 24b. Compound 24b exhibited potent HSL inhibitory activity (IC50=2nM) with a significantly reduced bioactivation potential. Oral administration of compound 24b exhibited an antilipolytic effect on rats at 3mg/kg.

Keywords

Boronic acid; Dyslipidemia; Hormone sensitive lipase; Lipolysis; Reactive metabolite.

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