title: Highly potent dipeptidyl peptidase IV inhibitors derived from Alogliptin through pharmacophore hybridization and lead optimization.
abstract: 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 Alogliptin was initiated and led to a novel DPP-IV inhibitor, 11a. Although it did not exhibit the desired activity (IC50=0.2 μM), compound 11a acts as a lead compound, which triggered a resulting structural optimization and the formation of compound 11m. 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.
authors.affiliation: First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Guangzhou 510120, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Xie
authors.forename: Lili
authors.initials: L
authors.lastname: Zeng
authors.forename: Shaogao
authors.initials: S
authors.lastname: Zeng
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.forename: Guicheng
authors.initials: G
authors.lastname: Zhang
authors.forename: Zhengchao
authors.initials: Z
authors.lastname: Tu
authors.forename: Hongjiang
authors.initials: H
authors.lastname: Xu
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.forename: Xiquan
authors.initials: X
authors.lastname: Zhang
authors.forename: Shanchun
authors.initials: S
authors.lastname: Wang
authors.forename: Wenhui
authors.initials: W
authors.lastname: Hu
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D020128:Inhibitory Concentration 50; D000069476:Linagliptin; D008297:Male; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D011687:Purines / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014498:Uracil / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D010880:Piperidines; D011687:Purines; D011799:Quinazolines; D000069476:Linagliptin; D014498:Uracil; C520853:alogliptin
keywords: DPP-IV inhibitor; In vivo; Pharmacophore hybridization; Superposition; Type 2 diabetes