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.
| Original language | English |
|---|---|
| Article number | 114837 |
| Journal | European Journal of Medicinal Chemistry |
| Volume | 244 |
| DOIs | |
| State | Published - 15 Dec 2022 |
Bibliographical note
Funding Information:Glutaminyl cyclase (QC) is a zinc-dependent aminoacyltransferase that converts the N-terminal glutamate residue of Aβ3-40/42 into the corresponding pyroglutamate form (pE-Aβ3-40/42) by intramolecular cyclization [16–18]. QC is more highly expressed in the brains and cerebrospinal fluid (CSF) of AD patients than control brains and can be detected in the early stages of AD [19,20]. In an AD mouse model, QC knockout was able to restore cognitive function [21], and QC inhibitors efficiently reduced the levels of pE-Aβ and Aβ plaques in the brain, resulting in improved memory deficits in AD mice [22–24]. These results support the use of QC inhibition as a viable disease-modifying therapy for AD [25].This work was supported by the Midcareer Researcher Program (NRF-2022R1A2C2004933) funded by the National Research Foundation of Korea (NRF).
Funding Information:
This work was supported by the Midcareer Researcher Program ( NRF-2022R1A2C2004933 ) funded by the National Research Foundation of Korea (NRF).
Publisher Copyright:
© 2022 Elsevier Masson SAS
