口服活性胃饥饿素受体反向激动剂及其对大鼠肥胖模型的作用。
Orally active ghrelin receptor inverse agonists and their actions on a rat obesity model.
作者信息
Takahashi Bitoku, Funami Hideaki, Iwaki Takehiko, Maruoka Hiroshi, Shibata Makoto, Koyama Makoto, Nagahira Asako, Kamiide Yoshiyuki, Kanki Satomi, Igawa Yoshiyuki, Muto Tsuyoshi
机构信息
Asubio Pharma Co., Ltd, 6-4-3, Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
Asubio Pharma Co., Ltd, 6-4-3, Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
出版信息
Bioorg Med Chem. 2015 Aug 1;23(15):4792-4803. doi: 10.1016/j.bmc.2015.05.047. Epub 2015 Jun 9.
A series of 2-alkylamino nicotinamide analogs was prepared as orally active ghrelin receptor (ghrelinR) inverse agonists. Starting from compound 1, oral bioavailability was improved by modifying metabolically unstable sites and reducing molecular weight. Brain-permeable compound 33 and compound 24 with low brain permeability were tested in rat models of obesity; 30 mg/kg of compound 33 suppressed weight gain. PK/PD analysis revealed that the anti-obesity effect of ghrelinR inverse agonists depends on their brain concentrations.
制备了一系列2-烷基氨基烟酰胺类似物作为具有口服活性的胃饥饿素受体（ghrelinR）反向激动剂。从化合物1开始，通过修饰代谢不稳定位点和降低分子量来提高口服生物利用度。在肥胖大鼠模型中测试了具有脑渗透性的化合物33和脑渗透性低的化合物24；30mg/kg的化合物33可抑制体重增加。药代动力学/药效学分析表明，ghrelinR反向激动剂的抗肥胖作用取决于其在脑中的浓度。
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