title: Identification of a novel hormone sensitive lipase inhibitor with a reduced potential of reactive metabolites formation.
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.
authors.affiliation: 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.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ogiyama
authors.affiliation: R&D Planning & Management Department, 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: Venture Science Laboratories, 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: Rare Disease & LCM Laboratories, 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: Biological Research Department, Daiichi Sankyo RD Novare Co., Ltd., 1-16-13, Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, 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: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Takakusa
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Shin-Ichi
authors.initials: SI
authors.lastname: Inoue
mesh_terms: D000284:Administration, Oral; D000818:Animals; D050171:Dyslipidemias / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D008297:Male; D066244:Proton Magnetic Resonance Spectroscopy; D051381:Rats; D017208:Rats, Wistar; D021241:Spectrometry, Mass, Electrospray Ionization; D002787:Sterol Esterase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D002787:Sterol Esterase
keywords: Boronic acid; Dyslipidemia; Hormone sensitive lipase; Lipolysis; Reactive metabolite