Application of classic medicinal chemistry strategies in the rapid generation of novel dipeptidylpeptidase-IV inhibitors 后印本

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.