Highly potent dipeptidyl peptidase Ⅳ inhibitors derived from Alogliptin through pharmacophore hybridization and lead optimization

摘要：

　　The superposition of the DPP-Ⅳ complex revealed that the butynyl group of Linagliptin can be freely switched with the cyanobenzyl group of Alogliptin.Thus, a pharmacophore hybridization of A logliptin was initiated and led to a novel DPP-Ⅳ inhibitor, 11a.Although it did not exhibit the desired activity (IC50=0.2 μM), compound 1 1a acts as a lead compound, which triggeied a resulting structural optimization and the formation of compound 1 1m.A novel series of potent DPP-Ⅳ inhibitors represented by compound 11m (IC50=0.4 nM) was ultimately obtained with a robust pharmacokinetic profile and superior in vitro and in vivo efficacy compared to Alogliptin.

关键词： DPP-Ⅳ inhibitor type 2 diabetes superposition pharmacophore hybridization in vivo

作者: Hui Xie Xiquan Zhang Shanchun Wang Wenhui Hu Lili Zeng Shaogao Zeng Xin Lu Xin Zhao Guicheng Zhang Zhengchao Tu Hongjiang Xu Ling Yang

作者单位: First Affiliated Hospital of Guangzhou Medical University,151 Yanjiang Road,Guangzhou,510120,China Jiangsu Chia-Tai Tianqing Pharmaceutical Co.Ltd,No.8 Julong North Rd.Xinpu Lianyungang Jiangsu,22200 Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Science,190 Kaiyuan Avenue,Guangzh

会议类型: 国内会议

会议名称: 2014年广东省药师周大会

会议地点: 广州

会议语种:英文

页码: 25-39

在线出版日期: 2014-01-11（万方平台首次上网日期，不代表论文的发表时间）