分类: 物理学 >> 普通物理:统计和量子力学,量子信息等 提交时间: 2017-11-17
摘要: A new chemical class of potent DPP-IV inhibitors has been structurally derived from our recently disclosed pyrrolopyrimidine scaffold by replacing cyanobenzyl with butynyl group. Systematic variations and structure-activity relationship studies have been conducted on the starting hit 51 (IC50= 0.46 μM). Consequently, compound 78 (IC50= 1.55 nM) was identified to be a potent, selective, and orally available lead, worth further evaluations and optimizations.
分类: 物理学 >> 普通物理:统计和量子力学,量子信息等 提交时间: 2017-11-17
摘要: The structural superposition of DPP-IV complex with Alogliptin and Linagliptin displayed a similar binding mode. The butynyl of Linagliptin and cyanobenzyl of Alogliptin occupy the S1 pocket which therefore could be mutually switched. Thus a pharmacophore hybridization of Alogliptin was initiated and led to a novel DPP-IV inhibitor 61. Though it did not exhibit desired activity (IC50= 0.2 礛), the butynyl compound acts as a lead compound triggered a following structural optimization. A novel series of potent DPP-IV inhibitors represented by compound 77 (IC50= 0.36 nM) were obtained with a robust pharmacokinetic profile and better in vitro and in vivo efficacy than Alogliptin.
分类: 生物学 >> 生态学 提交时间: 2017-11-17
摘要: The marketed DPP-IV inhibitors represented by Vildagliptin, Saxagliptin, and Alogliptin trigged the discovery of tens thousands of novel DPP-IV inhibitors. Inspired by the good potency and easily structural modification, we initiated a series of modification of Aloglitpin with classic medicinal chemistry strategies. Herein, we reviewed how we generated diverse and highly potent inhibitors X (IC50= 0.3 nM), Y (IC50= 3.6 nM), Z (IC50= nM), and E (IC50= 1.4 nM) through scaffold hopping triggered optimization, B (IC50= 0.7 nM), C (IC50= 0.4 nM), A (IC50= nM) through pharmacophorehybridization based lead generation, F (IC50= nM) via the extendedcombination of these strategies.In this way, the development of DPP-IV inhibitors will eventually become the classic case in themedicinal chemistry history like COX-2 inhibitors and sulfonamides.