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

Abstract

AbstractThe new high selective mAChRs M3 inhibitors with IC50 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 IC50 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.