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Potent human glutaminyl cyclase inhibitors as potential anti-Alzheimer's agents: Structure-activity relationship study of Arg-mimetic region

Title
Potent human glutaminyl cyclase inhibitors as potential anti-Alzheimer's agents: Structure-activity relationship study of Arg-mimetic region
Authors
Ngo, Van T. H.Van-Hai HoangPhuong-Thao TranAnn, JihyaeCui, MinghuaPark, GyungseoChoi, SunLee, JiyounKim, HeeHa, Hee-JinChoi, KwanghyunKim, Young-HoLee, Jeewoo
Ewha Authors
최선
SCOPUS Author ID
최선scopus
Issue Date
2018
Journal Title
BIOORGANIC & MEDICINAL CHEMISTRY
ISSN
0968-0896JCR Link

1464-3391JCR Link
Citation
BIOORGANIC & MEDICINAL CHEMISTRY vol. 26, no. 5, pp. 1035 - 1049
Keywords
Glutaminyl cyclase inhibitor; Alzheimer's disease; Beta-amyloid
Publisher
PERGAMON-ELSEVIER SCIENCE LTD
Indexed
SCI; SCIE; SCOPUS WOS scopus
Document Type
Article
Abstract
Pyroglutamate-modified amyloid beta peptides (pGlu-A beta) are highly neurotoxic and promote the formation of amyloid plaques. The pGlu-A beta peptides are generated by glutaminyl cyclase (QC), and recent clinical studies indicate that QC represents an alternative therapeutic target to treat Alzheimer's disease (AD). We have previously developed a series of QC inhibitors with an extended pharmacophoric scaffold, termed the Arg-mimetic D-region. In the present study, we focused on the structure activity relationship (SAR) of analogues with modifications in the D-region and evaluated their biological activity. Most compounds in this series exhibited potent activity in vitro, and our SAR analysis and the molecular docking studies identified compound 202 as a potential candidate because it forms an additional hydrophobic interaction in the hQC active site. Overall, our study provides valuable insights into the Arg-mimetic pharmacophore that will guide the design of novel QC inhibitors as potential treatments for AD. (C) 2018 Elsevier Ltd. All rights reserved.
DOI
10.1016/j.bmc.2018.01.015
Appears in Collections:
약학대학 > 약학과 > Journal papers
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