title: Discovery of Potent Human Glutaminyl Cyclase Inhibitors as Anti-Alzheimer's Agents Based on Rational Design.
abstract: Glutaminyl cyclase (QC) has been implicated in the formation of toxic amyloid plaques by generating the N-terminal pyroglutamate of β-amyloid peptides (pGlu-Aβ) and thus may participate in the pathogenesis of Alzheimer's disease (AD). We designed a library of glutamyl cyclase (QC) inhibitors based on the proposed binding mode of the preferred substrate, Aβ3E-42. An in vitro structure-activity relationship study identified several excellent QC inhibitors demonstrating 5- to 40-fold increases in potency compared to a known QC inhibitor. When tested in mouse models of AD, compound 212 significantly reduced the brain concentrations of pyroform Aβ and total Aβ and restored cognitive functions. This potent Aβ-lowering effect was achieved by incorporating an additional binding region into our previously established pharmacophoric model, resulting in strong interactions with the carboxylate group of Glu327 in the QC binding site. Our study offers useful insights in designing novel QC inhibitors as a potential treatment option for AD.
authors.affiliation: Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 08826, Republic of Korea.
authors.forename: Van-Hai
authors.initials: VH
authors.lastname: Hoang
authors.affiliation: Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 08826, Republic of Korea.|Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy , Hanoi, Vietnam.
authors.forename: Phuong-Thao
authors.initials: PT
authors.lastname: Tran
authors.affiliation: National Leading Research Laboratory of Molecular Modeling & Drug Design, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University , Seoul 03760, Republic of Korea.
authors.forename: Minghua
authors.initials: M
authors.lastname: Cui
authors.affiliation: Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 08826, Republic of Korea.
authors.forename: Van T H
authors.initials: VT
authors.lastname: Ngo
authors.affiliation: Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 08826, Republic of Korea.
authors.forename: Jihyae
authors.initials: J
authors.lastname: Ann
authors.affiliation: National Leading Research Laboratory of Molecular Modeling & Drug Design, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University , Seoul 03760, Republic of Korea.
authors.forename: Jongmi
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Global Medical Science, Sungshin University , Seoul 01133, Republic of Korea.
authors.forename: Jiyoun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Medifron DBT , Sandanro 349, Danwon-Gu, Ansan-City, Gyeonggi-Do 15426, Republic of Korea.
authors.forename: Kwanghyun
authors.initials: K
authors.lastname: Choi
authors.affiliation: Medifron DBT , Sandanro 349, Danwon-Gu, Ansan-City, Gyeonggi-Do 15426, Republic of Korea.
authors.forename: Hanyang
authors.initials: H
authors.lastname: Cho
authors.affiliation: Medifron DBT , Sandanro 349, Danwon-Gu, Ansan-City, Gyeonggi-Do 15426, Republic of Korea.
authors.forename: Hee
authors.initials: H
authors.lastname: Kim
authors.affiliation: Medifron DBT , Sandanro 349, Danwon-Gu, Ansan-City, Gyeonggi-Do 15426, Republic of Korea.
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Ha
authors.affiliation: Medifron DBT , Sandanro 349, Danwon-Gu, Ansan-City, Gyeonggi-Do 15426, Republic of Korea.
authors.forename: Hyun-Seok
authors.initials: HS
authors.lastname: Hong
authors.affiliation: National Leading Research Laboratory of Molecular Modeling & Drug Design, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University , Seoul 03760, Republic of Korea.
authors.forename: Sun
authors.identifier: 0000-0002-7669-7954
authors.initials: S
authors.lastname: Choi
authors.affiliation: Medifron DBT , Sandanro 349, Danwon-Gu, Ansan-City, Gyeonggi-Do 15426, Republic of Korea.
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 08826, Republic of Korea.
authors.forename: Jeewoo
authors.identifier: 0000-0002-7832-6719
authors.initials: J
authors.lastname: Lee
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001555:Benzene Derivatives / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D062105:Molecular Docking Simulation
chemical_list: D016229:Amyloid beta-Peptides; D001555:Benzene Derivatives; D004791:Enzyme Inhibitors; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase