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]
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- 作者：Yoshikazu Uto ; Yohei Kiyotsuka ; Yuko Ueno ; Yuriko Miyazawa ; Hitoshi Kurata ; Tsuneaki Ogata ; Tsuneo Deguchi ; Makiko Yamada ; Nobuaki Watanabe ; Masahiro Konishi ; Nobuya Kurikawa ; Toshiyuki Takagi ; Satoko
- 关键词：Stearoyl-CoA desaturase (SCD) ; Spiropiperidine ; Desaturation index
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2010
- 出版时间：15 January 2010
- 年：2010
- 卷：20
- 期：2
- 页码：746-754
- 全文大小：1855 K
文摘
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.