Author: Horak, Martin ; Hrabinova, Martina ; Korabecny, Jan ; Janousek, Jiri ; Kucera, Tomas ; Prchal, Lukas ; Makhaeva, Galina F ; Soukup, Ondrej ; Misiachna, Anna ; Mezeiova, Eva ; Fibigar, Jakub ; Pulkrabkova, Lenka ; Muckova, Lubica

The search for novel drugs to address the medical needs of Alzheimer's disease (AD) is an ongoing process relying on the discovery of disease-modifying agents. Given the complexity of the disease, such an aim can be pursued by developing so-called multi-target directed ligands (MTDLs) that will impact the disease pathophysiology more comprehensively. Herewith, we contemplated the therapeutic efficacy of an amiridine drug acting as a cholinesterase inhibitor by converting it into a novel class of novel MTDLs. Applying the linking approach, we have paired amiridine as a core building block with memantine/adamantylamine, trolox, and substituted benzothiazole moieties to generate novel MTDLs endowed with additional properties like N-methyl-d-aspartate (NMDA) receptor affinity, antioxidant capacity, and anti-amyloid properties, respectively. The top-ranked amiridine-based compound 5d was also inspected by in silico to reveal the butyrylcholinesterase binding differences with its close structural analogue 5b. Our study provides insight into the discovery of novel amiridine-based drugs by broadening their target-engaged profile from cholinesterase inhibitors towards MTDLs with potential implications in AD therapy.

01 Feb 2024·Archiv der Pharmazie

Conjugates of amiridine and thiouracil derivatives as effective inhibitors of butyrylcholinesterase with the potential to block β‐amyloid aggregation

Article

Author: Lushchekina, Sofya V ; Shchegolkov, Evgeny V ; Burgart, Yanina V ; Khudina, Olga G ; Borisevich, Sophia S ; Makhaeva, Galina F ; Rudakova, Elena V ; Grishchenko, Maria V ; Kovaleva, Nadezhda V ; Charushin, Valery N ; Boltneva, Natalia P ; Saloutin, Victor I

AbstractNew amiridine‐thiouracil conjugates with different substituents in the pyrimidine fragment (R = CH3, CF2Н, CF3, (CF2)2H) and different spacer lengths (n = 1–3) were synthesized. The conjugates rather weakly inhibit acetylcholinesterase (AChE) and exhibit high inhibitory activity (IC50 up to 0.752 ± 0.021 µM) and selectivity to butyrylcholinesterase (BChE), which increases with spacer elongation; the lead compounds are 11c, 12c, and 13c. The conjugates are mixed‐type reversible inhibitors of both cholinesterases and practically do not inhibit the structurally related off‐target enzyme carboxylesterase. The results of molecular docking to AChE and BChE are consistent with the experiment on enzyme inhibition and explain the structure–activity relationships, including the rather low anti‐AChE activity and the high anti‐BChE activity of long‐chain conjugates. The lead compounds displace propidium from the AChE peripheral anion site (PAS) at the level of the reference compound donepezil, which agrees with the mixed‐type mechanism of AChE inhibition and the main mode of binding of conjugates in the active site of AChE due to the interaction of the pyrimidine moiety with the PAS. This indicates the ability of the studied conjugates to block AChE‐induced aggregation of β‐amyloid, thereby exerting a disease‐modifying effect. According to computer calculations, all synthesized conjugates have an ADME profile acceptable for drugs.

01 Jan 2024·Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova

Role and place of ipidacrine in the therapy of diseases of the peripheral nervous system. The resolution of the expert council

Article

Author: Strokov, I A ; Churyukanov, M V ; Kozlov, I G ; Suponeva, N A ; Davydov, O S ; Amelin, A V ; Danilov, A B ; Zhivolupov, S A ; Shirokov, V A ; Kukushkin, M L

The resolution of the expert council is devoted to discussing aspects of the use of ipidacrine for the treatment of mononeuropathies, polyneuropathies and radiculopathies of various etiologies. Specialists prepared recommendations for ipidacrine's application in treating peripheral nervous system disorders.

100 Deals associated with Ipidacrine hydrochloride hydrate

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KEGG	Wiki	ATC	Drug Bank
D09750	Ipidacrine hydrochloride hydrate	N06DA05	DB13668

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	IND Application	CN	Jsc Olainfarm	29 Mar 2011
Alzheimer Disease	IND Application	CN	Younuokang (Beijing) Medical Technology Service Co., Ltd.	29 Mar 2011

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