2. Academic Validation
  3. Structure-activity relationship study of tryptophan-based butyrylcholinesterase inhibitors

Structure-activity relationship study of tryptophan-based butyrylcholinesterase inhibitors

  • Eur J Med Chem. 2020 Dec 15;208:112766. doi: 10.1016/j.ejmech.2020.112766.
Anže Meden 1,  Damijan Knez 1,  Natalia Malikowska-Racia 2,  Xavier Brazzolotto 3,  Florian Nachon 3,  Jurij Svete 4,  Kinga Sałat 2,  Uroš Grošelj 5,  Stanislav Gobec 6
Affiliations

Affiliations

  • 1 University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000, Ljubljana, Slovenia.
  • 2 Department of Pharmacodynamics, Chair of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688, Krakow, Poland.
  • 3 Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, 91223, Brétigny sur Orge, France.
  • 4 University of Ljubljana, Faculty of Chemistry and Chemical Technology, Večna Pot 113, SI-1000, Ljubljana, Slovenia.
  • 5 University of Ljubljana, Faculty of Chemistry and Chemical Technology, Večna Pot 113, SI-1000, Ljubljana, Slovenia. Electronic address: uros.groselj@fkkt.uni-lj.si.
  • 6 University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000, Ljubljana, Slovenia. Electronic address: stanislav.gobec@ffa.uni-lj.si.
PMID: 32919297 DOI: 10.1016/j.ejmech.2020.112766
Abstract

A series of tryptophan-based selective nanomolar butyrylcholinesterase (BChE) inhibitors was designed and synthesized. Compounds were optimized in terms of potency, selectivity, and synthetic accessibility. The crystal structure of the inhibitor 18 in complex with BChE revealed the molecular basis for its low nanomolar inhibition (IC50 = 2.8 nM). The favourable in vitro results enabled a first-in-animal in vivo efficacy and safety trial, which demonstrated a positive impact on fear-motivated and spatial long-term memory retrieval without any concomitant adverse motor effects. Altogether, this research culminated in a handful of new lead compounds with promising potential for symptomatic treatment of patients with Alzheimer's disease.

Keywords

Alzheimer’s disease; Butyrylcholinesterase; Cholinesterase inhibitors; Neurodegenerative diseases.

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