Design, synthesis, and pharmacological evaluation of a novel series of hormone sensitive lipase inhibitor

Tomoko Ogiyama; Mitsuhiro Yamaguchi; Nobuya Kurikawa; Shoko Honzumi; Koji Terayama; Nobumi Nagaoka; Yuka Yamamoto; Takako Kimura; Daisuke Sugiyama; Shin-Ichi Inoue

doi:10.1016/j.bmc.2017.07.028

Design, synthesis, and pharmacological evaluation of a novel series of hormone sensitive lipase inhibitor

Bioorg Med Chem. 2017 Sep 1;25(17):4817-4828. doi: 10.1016/j.bmc.2017.07.028. Epub 2017 Jul 17.

Authors

Affiliations

¹ Modality Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: yamamoto.tomoko.me@daiichisankyo.co.jp.
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 End-Organ Disease Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
⁶ Modality Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
⁷ Biological Research Department, Daiichi Sankyo RD Novare Co., Ltd., 1-16-13, Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan.
⁸ Organic Synthesis Department, Daiichi Sankyo RD Novare Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
⁹ Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.

PMID: 28756012
DOI: 10.1016/j.bmc.2017.07.028

Abstract

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.

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

MeSH terms

Acetylcholinesterase / chemistry
Acetylcholinesterase / metabolism
Administration, Oral
Animals
Butyrylcholinesterase / chemistry
Butyrylcholinesterase / metabolism
Drug Design*
Enzyme Activation / drug effects
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / pharmacology
Glutathione / chemistry
Glutathione / metabolism
Glycerol / blood
Half-Life
Humans
Hypolipidemic Agents / chemical synthesis*
Hypolipidemic Agents / chemistry
Hypolipidemic Agents / pharmacokinetics
Hypolipidemic Agents / pharmacology*
Inhibitory Concentration 50
Male
Rats
Rats, Wistar
Recombinant Proteins / biosynthesis
Recombinant Proteins / chemistry
Recombinant Proteins / isolation & purification
Sterol Esterase / antagonists & inhibitors*
Sterol Esterase / genetics
Sterol Esterase / metabolism
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Hypolipidemic Agents
Recombinant Proteins
Sterol Esterase
Acetylcholinesterase
Butyrylcholinesterase
Glutathione
Glycerol