Suzuki Takao, Kameda Minoru, Ando Makoto, Miyazoe Hiroshi, Sekino Etsuko, Ito Satoru, Masutani Kouta, Kamijo Kaori, Takezawa Akihiro, Moriya Minoru, Ito Masahiko, Ito Junko, Nakase Kazuho, Matsushita Hiroko, Ishihara Akane, Takenaga Norihiro, Tokita Shigeru, Kanatani Akio, Sato Nagaaki, Fukami Takehiro
Department of Medicinal Chemistry, Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan.
Bioorg Med Chem Lett. 2009 Sep 15;19(18):5339-45. doi: 10.1016/j.bmcl.2009.07.132. Epub 2009 Aug 6.
Optimization of the lead 2a led to the identification of a novel diarylketoxime class of melanin-concentrating hormone 1 receptor (MCH-1R) antagonists. Our focus was directed toward improvement of hERG activity and metabolic stability. The representative derivative 4b showed potent and dose-dependent body weight reduction in diet-induced obese (DIO) C57BL/6J mice after oral administration. The synthesis and structure-activity relationships of the novel diarylketoxime MCH-1R antagonists are described.
对先导化合物2a进行优化后，鉴定出了一类新型的二芳基酮肟类黑色素浓缩激素1受体（MCH-1R）拮抗剂。我们的重点是改善人乙醚相关基因（hERG）活性和代谢稳定性。代表性衍生物4b在口服给药后，能使饮食诱导肥胖（DIO）的C57BL/6J小鼠体重显著且呈剂量依赖性降低。本文描述了新型二芳基酮肟类MCH-1R拮抗剂的合成及其构效关系。
