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Discovery and evaluation of enantiopure 9H-pyrimido[4,5‐b]indoles as nanomolar GSK‐3β inhibitors with improved metabolic stability
- Source :
- International Journal of Molecular Sciences, Volume 21, Issue 21, International Journal of Molecular Sciences, Vol 21, Iss 7823, p 7823 (2020)
- Publication Year :
- 2020
-
Abstract
- Glycogen synthase kinase-3&beta<br />(GSK-3&beta<br />) is a potential target in the field of Alzheimer&rsquo<br />s disease drug discovery. We recently reported a new class of 9H-pyrimido[4,5-b]indole-based GSK-3&beta<br />inhibitors, of which 3-(3-((7-chloro-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)propanenitrile (1) demonstrated promising inhibitory potency. However, this compound underwent rapid degradation by human liver microsomes. Starting from 1, we prepared a series of amide-based derivatives and studied their structure&ndash<br />activity relationships against GSK-3&beta<br />supported by 1 &micro<br />s molecular dynamics simulations. The biological potency of this series was substantially enhanced by identifying the eutomer configuration at the stereocenter. Moreover, the introduction of an amide bond proved to be an effective strategy to eliminate the metabolic hotspot. The most potent compounds, (R)-3-(3-((7-chloro-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)-3-oxopropanenitrile ((R)-2) and (R)-1-(3-((7-bromo-9Hpyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)propan-1-one ((R)-28), exhibited IC50 values of 480 nM and 360 nM, respectively, and displayed improved metabolic stability. Their favorable biological profile is complemented by minimal cytotoxicity and neuroprotective properties.
- Subjects :
- Male
9H‐pyrimido[4,5‐b] indole
Indoles
9H-pyrimido[4,5-b]indole
Drug Evaluation, Preclinical
CHO Cells
Molecular Dynamics Simulation
Article
Protein kinase
Cell Line
glycogen synthase kinase-3β
lcsh:Chemistry
Structure-Activity Relationship
Cricetulus
Drug Stability
Glycogen synthase kinase‐3β
Drug Discovery
Animals
Humans
lcsh:QH301-705.5
Protein Kinase Inhibitors
Kinase inhibitor
Glycogen Synthase Kinase 3 beta
lcsh:Biology (General)
lcsh:QD1-999
Microsomes, Liver
Female
Metabolic stability
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences, Volume 21, Issue 21, International Journal of Molecular Sciences, Vol 21, Iss 7823, p 7823 (2020)
- Accession number :
- edsair.pmid.dedup....f96ca3718f42f0614b0557b3c394d9ce