title: Identification of a novel boronic acid as a potent, selective, and orally active hormone sensitive lipase inhibitor.
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.
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: yamamoto.tomoko.me@daiichisankyo.co.jp.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ogiyama
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yamaguchi
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Kurikawa
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Honzumi
authors.affiliation: Daiichi Sankyo RD Novare Co., Ltd., 1-16-13, Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sugiyama
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Inoue
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001897:Boronic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D066244:Proton Magnetic Resonance Spectroscopy; D051381:Rats; D017208:Rats, Wistar; D021241:Spectrometry, Mass, Electrospray Ionization; D002787:Sterol Esterase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D001897:Boronic Acids; D004791:Enzyme Inhibitors; D002787:Sterol Esterase
keywords: Boronic acid; Dyslipidemia; Hormone sensitive lipase (HSL); Lipolysis