Novel indanone derivatives as MAO B/H3 R dual-targeting ligands for treatment of Parkinson's disease

European Journal of Medicinal Chemistry
Anna AffiniHolger Stark

Abstract

The design of multi-targeting ligands was developed in the last decades as an innovative therapeutic concept for Parkinson's disease (PD) and other neurodegenerative disorders. As the monoamine oxidase B (MAO B) and the histamine H3receptor (H3R) are promising targets for dopaminergic regulation, we synthetized dual-targeting ligands (DTLs) as non-dopaminergic receptor approach for the treatment of PD. Three series of compounds were developed by attaching the H3R pharmacophore to indanone-related MAO B motifs, leading to development of MAO B/H3R DTLs. Among synthesized indanone DTLs, compounds bearing the 2-benzylidene-1-indanone core structure showed MAO B preferring inhibition capabilities along with nanomolar hH3R affinity. Substitution of C5 and C6 position of the 2-benzylidene-1-indanones with lipophilic substituents revealed three promising candidates exhibiting inhibitory potencies for MAO B with IC50values ranging from 1931 nM to 276 nM and high affinities at hH3R (Ki < 50 nM). Compound 3f ((E)-5-((4-bromobenzyl)oxy)-2-(4-(3-(piperidin-1-yl)propoxy)benzylidene)-2,3-dihydro-1H-inden-1-one, MAO B IC50 = 276 nM, hH3R Ki = 6.5 nM) showed highest preference for MAO B over MAO A (SI > 36). Interestingly, IC50determinations af...Continue Reading

Citations

May 16, 2020·International Journal of Molecular Sciences·Dorota ŁażewskaKatarzyna Kieć-Kononowicz
Jan 4, 2019·Medicinal Research Reviews·Rati Kailash Prasad Tripathi, Senthil Raja Ayyannan
Feb 17, 2021·Molecular Psychiatry·Ioannis MantasPer Svenningsson
Jun 10, 2021·Journal of Medicinal Chemistry·Stefanie HagenowHolger Stark
Jul 3, 2021·Biomolecules·Oliwia KoszłaAgnieszka A Kaczor
May 15, 2019·Journal of Medicinal Chemistry·Junting ZhouHaopeng Sun

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