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].
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.
Uto
Yoshikazu
Y
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
Kiyotsuka
Yohei
Y
Ueno
Yuko
Y
Miyazawa
Yuriko
Y
Kurata
Hitoshi
H
Ogata
Tsuneaki
T
Deguchi
Tsuneo
T
Yamada
Makiko
M
Watanabe
Nobuaki
N
Konishi
Masahiro
M
Kurikawa
Nobuya
N
Takagi
Toshiyuki
T
Wakimoto
Satoko
S
Kono
Keita
K
Ohsumi
Jun
J
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
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