Bioorganic and Medicinal Chemistry Letters p. 746 - 754 (2010)
Update date:2022-09-26
Topics:
Uto, Yoshikazu
Kiyotsuka, Yohei
Ueno, Yuko
Miyazawa, Yuriko
Kurata, Hitoshi
Ogata, Tsuneaki
Deguchi, Tsuneo
Yamada, Makiko
Watanabe, Nobuaki
Konishi, Masahiro
Kurikawa, Nobuya
Takagi, Toshiyuki
Wakimoto, Satoko
Kono, Keita
Ohsumi, Jun
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/6 J mice). With regard to the pharmacological evaluation, 19 showed powerful reduction of the desaturation index in the plasma of C57BL/6 J 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 (3 mg/kg) in our preliminary analysis.
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