title: Novel spiropiperidine-based stearoyl-CoA desaturase-1 inhibitors: Identification of 1'-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4'-piperidine].
abstract: Cyclization of the benzoylpiperidine in lead compound 2 generated a series of novel and highly potent spiropiperidine-based stearoyl-CoA desaturase (SCD)-1 inhibitors. Among them, 1'-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4'-piperidine] (19) demonstrated the most powerful inhibitory activity against SCD-1, not only in vitro but also in vivo (C57BL/6J mice). With regard to the pharmacological evaluation, 19 showed powerful reduction of the desaturation index in the plasma of C57BL/6J mice on a non-fat diet after a 7-day oral administration (q.d.) without causing notable abnormalities in the eyes or skin up to the highest dose (3mg/kg) in our preliminary analysis.
authors.affiliation: Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co. Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. uto.yoshikazu.pw@daiichisankyo.co.jp
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Uto
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kiyotsuka
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ueno
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Miyazawa
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kurata
authors.forename: Tsuneaki
authors.initials: T
authors.lastname: Ogata
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Deguchi
authors.forename: Makiko
authors.initials: M
authors.lastname: Yamada
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Watanabe
authors.forename: Masahiro
authors.initials: M
authors.lastname: Konishi
authors.forename: Nobuya
authors.initials: N
authors.lastname: Kurikawa
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takagi
authors.forename: Satoko
authors.initials: S
authors.lastname: Wakimoto
authors.forename: Keita
authors.initials: K
authors.lastname: Kono
authors.forename: Jun
authors.initials: J
authors.lastname: Ohsumi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C548720:1'-(6-(5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl)pyridazin-3-yl)-5-(trifluoromethyl)-3,4-dihydrospiro(chromene-2,4'-piperidine); D001578:Benzopyrans; D010880:Piperidines; D013230:Stearoyl-CoA Desaturase