Computer-aided design of muscarinic acetylcholine receptor M3 inhibitors: Promising compounds among trifluoromethyl containing hexahydropyrimidinones/thiones.

Autor: Nyporko A; Taras Shevchenko National University of Kyiv, Kyiv, 01033, Ukraine., Tsymbalyuk O; Taras Shevchenko National University of Kyiv, Kyiv, 01033, Ukraine., Voiteshenko I; Taras Shevchenko National University of Kyiv, Kyiv, 01033, Ukraine., Starosyla S; Receptor.AI Inc., 20-22 Wenlock Road, London, N1 7GU, United Kingdom., Protopopov M; Chemspace LLC, Kyiv, Ukraine., Bdzhola V; Institute of Molecular Biology and Genetics, NAS of Ukraine, Kyiv, 03143, Ukraine.
Jazyk: angličtina
Zdroj: Molecular informatics [Mol Inform] 2023 Aug; Vol. 42 (8-9), pp. e2300006. Date of Electronic Publication: 2023 Aug 09.
DOI: 10.1002/minf.202300006
Abstrakt: The new high selective mAChRs M3 inhibitors with IC 50 in nanomolecular ranges, which can be the prototypes for effective COPD and asthma treatment drugs, were discovered with computational approaches among trifluoromethyl containing hexahydropyrimidinones/thiones. Compounds [6-(4-ethoxy-3-methoxy-phenyl)-4-hydroxy-2-thioxo-4-(trifluoromethyl)hexahydropyrimidin-5-yl]-phenyl-methanone (THPT-1) and 5-benzoyl-6-(3,4-dimethoxyphenyl)-4-hydroxy-4-(trifluoromethyl)hexahydropyrimidin-2-one (THPO-4) have been proved to be a highly effective (with IC 50 values of 1.62 ⋅ 10 -7  M and 3.09 ⋅ 10 -9  M, respectively) at the same concentrations significantly competitive inhibit the signal conduction through mAChR3 in comparison with ipratropium bromide, without significant effect on mAChR2, nicotinic cholinergic and adrenergic receptors.
(© 2023 Wiley-VCH GmbH.)
Databáze: MEDLINE
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