title: Discovery of potent dipeptidyl peptidase IV inhibitors through pharmacophore hybridization and hit-to-lead optimization.
abstract: A novel dipeptidyl peptidase IV inhibitor hit (5, IC50=0.86 μM) was structurally derived from our recently disclosed preclinical candidate 4 by replacing the cyanobenzyl with a butynyl based on pharmacophore hybridization. A hit-to-lead optimization effort was then initiated to improve its potency. Most N-substituted analogs exhibited good in vitro activity, and compound 18o (IC50=1.55 nM) was identified to be a potent dipeptidyl peptidase IV inhibitor with a significantly improved pharmacokinetic properties (bioavailablity: 41% vs 82.9%; T1/2: 2h vs 4.9h).
authors: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou 510530, China.
authors: Shaogao
authors: S
authors: Zeng
authors: Hui
authors: H
authors: Xie
authors: Li-li
authors: LL
authors: Zeng
authors: Xin
authors: X
authors: Lu
authors: Xin
authors: X
authors: Zhao
authors: Gui-cheng
authors: GC
authors: Zhang
authors: Zheng-chao
authors: ZC
authors: Tu
authors: Hong-jiang
authors: HJ
authors: Xu
authors: Ling
authors: L
authors: Yang
authors: Xi-quan
authors: XQ
authors: Zhang
authors: Wenhui
authors: W
authors: Hu
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D018819:Dipeptidyl Peptidase 4