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Scaffold Hopping from Amodiaquine to Novel Nurr1 Agonist Chemotypes via Microscale Analogue Libraries
Author(s) -
Willems Sabine,
Müller Marcel,
Ohrndorf Julia,
Heering Jan,
Proschak Ewgenij,
Merk Daniel
Publication year - 2022
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202200026
Subject(s) - chemotype , scaffold , agonist , chemistry , microscale chemistry , stereochemistry , computational biology , computer science , biology , biochemistry , mathematics , receptor , programming language , mathematics education , chromatography , essential oil
Abstract Several lines of evidence suggest the ligand‐sensing transcription factor Nurr1 as a promising target to treat neurodegenerative diseases. Nurr1 modulators to validate and exploit this therapeutic potential are rare, however. To identify novel Nurr1 agonist chemotypes, we have employed the Nurr1 activator amodiaquine as template for microscale analogue library synthesis. The first set of analogues was based on the 7‐chloroquiolin‐4‐amine core fragment of amodiaquine and revealed superior N‐substituents compared to diethylaminomethylphenol contained in the template. A second library of analogues was subsequently prepared to replace the chloroquinolineamine scaffold. The two sets of analogues enabled a full scaffold hop from amodiaquine to a novel Nurr1 agonist sharing no structural features with the lead but comprising superior potency on Nurr1. Additionally, pharmacophore modeling based on the entire set of active and inactive analogues suggested key features for Nurr1 agonists.