2. Academic Validation
  3. Discovery of potent indazole-based human glutaminyl cyclase (QC) inhibitors as Anti-Alzheimer's disease agents

Discovery of potent indazole-based human glutaminyl cyclase (QC) inhibitors as Anti-Alzheimer's disease agents

  • Eur J Med Chem. 2022 Dec 15;244:114837. doi: 10.1016/j.ejmech.2022.114837.
Nguyen Van Manh 1,  Van-Hai Hoang 2,  Van T H Ngo 3,  Soosung Kang 4,  Jin Ju Jeong 5,  Hee-Jin Ha 6,  Hee Kim 6,  Young-Ho Kim 6,  Jihyae Ann 7,  Jeewoo Lee 8
Affiliations

Affiliations

  • 1 Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
  • 2 Faculty of Pharmacy & PHENIKAA Institute for Advanced Study (PIAS), PHENIKAA University, Hanoi, 12116, Viet Nam.
  • 3 Graduate Department of Healthcare Science, Dai Nam University, Hanoi, Viet Nam.
  • 4 College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea.
  • 5 Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea; JMackem Co. Ltd, Seoul, 08826, Republic of Korea.
  • 6 Medifron DBT, Seoul, 08502, Republic of Korea.
  • 7 Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea; JMackem Co. Ltd, Seoul, 08826, Republic of Korea. Electronic address: jihuya@snu.ac.kr.
  • 8 Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea. Electronic address: jeewoo@snu.ac.kr.
PMID: 36265279 DOI: 10.1016/j.ejmech.2022.114837
Abstract

The toxic pyroglutamate form of Amyloid-β (pE-Aβ) is important for the pathogenesis of early Alzheimer's disease (AD); therefore, reducing pE-Aβ by inhibiting glutaminyl cyclase (QC) provides a promising strategy for developing disease-modifying AD drugs. In this study, potent and selective QC inhibitors with desirable drug-like properties were discovered by replacing the 3,4-dimethoxyphenyl group in a QC inhibitor with a bioisosteric indazole surrogate. Among them, 3-methylindazole-6-yl and 3-methylindazole-5-yl derivatives with an N-cyclohexylurea were identified as highly potent inhibitors with IC50 values of 3.2 nM and 2.3 nM, respectively, both of which were approximately 10-fold more potent than varoglutamstat. In addition, the three inhibitors significantly reduced pE-Aβ3-40 levels in an acute animal model after intracerebroventricular (icv) injection and were selective for hQC. Further in vitro pharmacokinetic and toxicity studies, including those investigating cytotoxicity, hERG inhibition, blood-brain barrier (BBB) permeability and metabolic stability, indicated that N-(3-methylindazole-6-yl)-N'-(cyclohexyl)urea derivative exhibited the most promising efficacy, selectivity and drug-like profile; thus, it was evaluated for its in vivo efficacy in an AD model.

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