Carltonine-derived compounds for targeted butyrylcholinesterase inhibition

Pidany, Filip; Kroustkova, Jana; Jenco, Jaroslav; Breiterova, Katerina Hradiska; Muckova, Lubica; Novakova, Lucie; Kunes, Jiri; Fibigar, Jakub; Kucera, Tomas; Novak, Martin; Sorf, Ales; Hrabinova, Martina; Pulkrabkova, Lenka; Janousek, Jiri; Soukup, Ondrej; Jun, Daniel; Korabecny, Jan; Cahlikova, Lucie

doi:10.1039/d4md00060a

RSC Med. Chem.

2024

DOI: 10.1039/d4md00060a

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Carltonine-derived compounds for targeted butyrylcholinesterase inhibition

Filip Pidany,

Jana Kroustkova,

Jaroslav Jenco

et al.

Abstract: The investigation into human butyrylcholinesterase (hBChE) inhibitors as therapeutic agents for Alzheimer's disease (AD) holds significant promise, addressing both symptomatic relief and disease progression. In the pursuit of novel drug...

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Stepwise Structural Simplification of the Dihydroxyanthraquinone Moiety of a Multitarget Rhein-Based Anti-Alzheimer Lead to Improve Drug Metabolism and Pharmacokinetic Properties

Pont,

Sampietro,

Pérez-Areales

et al. 2024

Pharmaceutics

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Multitarget compounds have emerged as promising drug candidates to cope with complex multifactorial diseases, like Alzheimer’s disease (AD). Most multitarget compounds are designed by linking two pharmacophores through a tether chain (linked hybrids), which results in rather large molecules that are particularly useful to hit targets with large binding cavities, but at the expense of suffering from suboptimal physicochemical/pharmacokinetic properties. Molecular size reduction by removal of superfluous structural elements while retaining the key pharmacophoric motifs may represent a compromise solution to achieve both multitargeting and favorable physicochemical/PK properties. Here, we report the stepwise structural simplification of the dihydroxyanthraquinone moiety of a rhein–huprine hybrid lead by hydroxy group removal—ring contraction—ring opening—ring removal, which has led to new analogs that retain or surpass the potency of the lead on its multiple AD targets while exhibiting more favorable drug metabolism and pharmacokinetic (DMPK) properties and safety profile. In particular, the most simplified acetophenone analog displays dual nanomolar inhibition of human acetylcholinesterase and butyrylcholinesterase (IC50 = 6 nM and 13 nM, respectively), moderately potent inhibition of human BACE-1 (48% inhibition at 15 µM) and Aβ42 and tau aggregation (73% and 68% inhibition, respectively, at 10 µM), favorable in vitro brain permeation, higher aqueous solubility (18 µM) and plasma stability (100/96/86% remaining in human/mouse/rat plasma after 6 h incubation), and lower acute toxicity in a model organism (zebrafish embryos; LC50 >> 100 µM) than the initial lead, thereby confirming the successful lead optimization by structural simplification.

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Stepwise Structural Simplification of the Dihydroxyanthraquinone Moiety of a Multitarget Rhein-Based Anti-Alzheimer Lead to Improve Drug Metabolism and Pharmacokinetic Properties

Pont,

Sampietro,

Pérez-Areales

et al. 2024

Pharmaceutics

View full text Add to dashboard Cite

show abstract

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Carltonine-derived compounds for targeted butyrylcholinesterase inhibition

Abstract: The investigation into human butyrylcholinesterase (hBChE) inhibitors as therapeutic agents for Alzheimer's disease (AD) holds significant promise, addressing both symptomatic relief and disease progression. In the pursuit of novel drug...

Cited by 1 publication

References 86 publications

Stepwise Structural Simplification of the Dihydroxyanthraquinone Moiety of a Multitarget Rhein-Based Anti-Alzheimer Lead to Improve Drug Metabolism and Pharmacokinetic Properties

Stepwise Structural Simplification of the Dihydroxyanthraquinone Moiety of a Multitarget Rhein-Based Anti-Alzheimer Lead to Improve Drug Metabolism and Pharmacokinetic Properties

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