| Title | Synthesis and Evaluation of Diphenyl Conjugated Imidazole Derivatives as Potential Glutaminyl Cyclase Inhibitors for Treatment of Alzheimer's Disease |
| Authors | Li, Manman Dong, Yao Yu, Xi Li, Yue Zou, Yongdong Zheng, Yizhi He, Zhendan Liu, Zhigang Quan, Junmin Bu, Xianzhang Wu, Haiqiang |
| Affiliation | Shenzhen Univ, Sch Med, Dept Pharm, Shenzhen 518060, Peoples R China. Shenzhen Univ, Coll Life Sci & Oceanog, Shenzhen 518060, Peoples R China. Shenzhen Univ, Sch Med, Shenzhen 518060, Peoples R China. Peking Univ, Shenzhen Grad Sch, Sch Chem Biol & Biotechnol, Key Lab Struct Biol, Shenzhen 518055, Peoples R China. Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangzhou 510006, Guangdong, Peoples R China. Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. Shenzhen Univ, Sch Med, Dept Pharm, Shenzhen 518060, Peoples R China. Wu, HQ (reprint author), Shenzhen Univ, Coll Life Sci & Oceanog, Shenzhen 518060, Peoples R China. Wu, HQ (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. |
| Keywords | MEMBRANE-PERMEABILITY ASSAY PYROGLUTAMATE-A-BETA AMYLOID-BETA AGGREGATION EXPRESSION HYPOTHESIS PEPTIDES BLOOD BOND |
| Issue Date | 2017 |
| Publisher | JOURNAL OF MEDICINAL CHEMISTRY |
| Citation | JOURNAL OF MEDICINAL CHEMISTRY.2017,60(15),6664-6677. |
| Abstract | High expression of glutaminyl cyclase (QC) contributes to the initiation of Alzheimer's disease (AD) by catalyzing the generation of neurotoxic pyroglutamate (pE)-modified beta-amyloid (A beta) peptides. Preventing the generation of pE-A beta s by QC inhibition has been suggested as a novel approach to a disease-modifying therapy for AD. In this work, a series of diphenyl conjugated imidazole derivatives (DPCIs) was rationally designed and synthesized. Analogues with this scaffold exhibited potent inhibitory activity against human QC (hQC) and good in vitro blood brain barrier (BBB) permeability. Further assessments corroborated that the selected hQC inhibitor 28 inhibits the activity of hQC, dramatically reduces the generation of pE-A beta s in cultured cells and in vivo, and improves the behavior of AD mice. |
| URI | http://hdl.handle.net/20.500.11897/471533 |
| ISSN | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.7b00648 |
| Indexed | SCI(E) |
| Appears in Collections: | 化学生物学与生物技术学院 |
