2. Academic Validation
  3. Discovery of Conformationally Restricted Human Glutaminyl Cyclase Inhibitors as Potent Anti-Alzheimer's Agents by Structure-Based Design

Discovery of Conformationally Restricted Human Glutaminyl Cyclase Inhibitors as Potent Anti-Alzheimer's Agents by Structure-Based Design

  • J Med Chem. 2019 Sep 12;62(17):8011-8027. doi: 10.1021/acs.jmedchem.9b00751.
Van-Hai Hoang 1,  Van T H Ngo 2,  Minghua Cui 3,  Nguyen Van Manh 1,  Phuong-Thao Tran 4,  Jihyae Ann 1,  Hee-Jin Ha 5,  Hee Kim 5,  Kwanghyun Choi 5,  Young-Ho Kim 5,  Hyerim Chang 3,  Stephani Joy Y Macalino 3,  Jiyoun Lee 6,  Sun Choi 3,  Jeewoo Lee 1
Affiliations

Affiliations

  • 1 Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy , Seoul National University , Seoul 08826 , Republic of Korea.
  • 2 Laboratory of Theoretical and Computational Biophysics & Faculty of Pharmacy , Ton Duc Thang University , Ho Chi Minh City 75307 , Vietnam.
  • 3 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.
  • 4 Department of Pharmaceutical Chemistry , Hanoi University of Pharmacy , Hanoi 10000 , Vietnam.
  • 5 Medifron DBT , Sandanro 349 , Danwon-Gu, Ansan-City , Gyeonggi-Do 15426 , Republic of Korea.
  • 6 Department of Global Medical Science , Sungshin University , Seoul 01133 , Republic of Korea.
PMID: 31411468 DOI: 10.1021/acs.jmedchem.9b00751
Abstract

Alzheimer's disease (AD) is an incurable, progressive neurodegenerative disease whose pathogenesis cannot be defined by one single element but consists of various factors; thus, there is a call for alternative approaches to tackle the multifaceted aspects of AD. Among the potential alternative targets, we aim to focus on glutaminyl cyclase (QC), which reduces the toxic pyroform of β-amyloid in the brains of AD patients. On the basis of a putative active conformation of the prototype inhibitor 1, a series of N-substituted thiourea, urea, and α-substituted amide derivatives were developed. The structure-activity relationship analyses indicated that conformationally restrained inhibitors demonstrated much improved QC inhibition in vitro compared to nonrestricted analogues, and several selected compounds demonstrated desirable therapeutic activity in an AD mouse model. The conformational analysis of a representative inhibitor indicated that the inhibitor appeared to maintain the Z-E conformation at the active site, as it is critical for its potent activity.

Figures