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Novel benzoylpiperidine-based stearoyl-CoA desaturase-1 inhibitors: Identification of 6-[4-(2-methylbenzoyl)piperidin-1-yl]pyridazine-3-carboxylic acid (2-hydroxy-2-pyridin-3-ylethyl)amide and its plasma triglyceride-lowering effects in Zucker fatty rats |
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| Authors: | Yoshikazu Uto Tsuneaki Ogata Yohei Kiyotsuka Yuko Ueno Yuriko Miyazawa Hitoshi Kurata Tsuneo Deguchi Nobuaki Watanabe Masahiro Konishi Ryo Okuyama Nobuya Kurikawa Toshiyuki Takagi Satoko Wakimoto Jun Ohsumi |
| Institution: | 1. Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co. Ltd, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan;2. Global Project Management Department, Daiichi Sankyo Co. Ltd, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan;3. Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co. Ltd, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan;4. Biological Research Laboratories II, Daiichi Sankyo Co. Ltd, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan;5. Clinical Development Department I, Daiichi Sankyo Co. Ltd, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan |
| Abstract: | Starting from a known piperazine-based SCD-1 inhibitor, we obtained more potent benzoylpiperidine analogs. Optimization of the structure of the benzoylpiperidine-based SCD-1 inhibitors resulted in the identification of 6-4-(2-methylbenzoyl)piperidin-1-yl]pyridazine-3-carboxylic acid (2-hydroxy-2-pyridin-3-yl-ethyl)amide (24) which showed strong inhibitory activity against both human and murine SCD-1. In addition, this compound exhibited good oral bioavailability and demonstrated plasma triglyceride lowering effects in Zucker fatty rats in a dose-dependent manner after a 7-day oral administration (qd). |
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