TY  - JOUR
A1  - Willems, Sabine
A1  - Müller, Marcel
A1  - Ohrndorf, Julia
A1  - Heering, Jan Peter
A1  - Proschak, Ewgenij
A1  - Merk, Daniel
T1  - Scaffold hopping from amodiaquine to novel Nurr1 agonist chemotypes via microscale analogue libraries
T2  - ChemMedChem
N2  - 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.
KW  - nuclear receptor-related 1
KW  - NR4A2
KW  - transcription factor
KW  - neurodegeneration
KW  - pharmacophore model
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/75499
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-754995
SN  - 1860-7187
N1  - This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 875510. Open Access funding enabled and organized by Projekt DEAL.
VL  - 17.2022
IS  - 8, e202200026
SP  - 1
EP  - 10
PB  - Wiley-VCH
CY  - Weinheim
ER  -