Pyrrolinone derivatives as a new class of P2X3 receptor antagonists. Part 1: Initial structure-activity relationship studies of a hit from a high throughput screening

Amination of 5-Spiro-Substituted 3-Hydroxy-1,5-dihydro-2H-pyrrol-2-ones

“…Then, we performed a series of reactions of compound 1a with cyclohexylamine ( Table 1 ) in order to obtain the required cyclohexylamino derivative 3a . The examined conditions ( Table 1 ) were selected according to the previously reported substitution reactions of hydroxyl groups in various non-spiro HDPs (bearing hydrogen and a substituent at the C 5 position) with amines [ 1 , 2 , 7 , 9 , 10 , 11 , 12 ]. Although the examined conditions were productive in the reported cases [ 1 , 2 , 7 , 9 , 10 , 11 , 12 ], in our study, none of them led to the desired results ( Table 1 ).…”

“…The 3-hydroxy-1,5-dihydro-2 H -pyrrol-2-one (HDP) motif ( Figure 1 ) is a valuable scaffold in drug discovery. Inhibitors of p53–MDM2 protein–protein interaction [ 1 , 2 ], inhibitors of HIV integrase [ 3 , 4 ], antibacterial agents against methicillin-resistant Staphylococcus aureus [ 5 ], dengue virus helicase inhibitors [ 6 ], P2X3 receptor antagonists [ 7 ], and other potential pharmaceuticals [ 8 , 9 ] have been developed on its basis.…”

“…There are three universal strategies towards ADPs enabling their synthesis with a wide range of substituents ( Scheme 1 ). These strategies are the substitution of hydroxyl groups in the corresponding HDPs via their reactions with amines (pathway a ) [ 1 , 2 , 7 , 9 , 10 , 11 , 12 ], the multicomponent reactions of amines and aldehydes with pyruvic acid derivatives (pathway b ) [ 13 , 14 ] or acetylenedicarboxylates (pathway c ) [ 15 , 16 ] ( Scheme 1 ).…”

“…As a part of our long-standing interest in the synthesis of spiro compounds bearing the HDP moiety [ 17 ], we wanted to prepare their 3-amino analogs. However, we were unable to synthesize the desired compounds from HDPs and amines [ 1 , 2 , 7 , 9 , 10 , 11 , 12 ], and therefore, herein, we report an alternative approach to ADPs ( Scheme 2 ).…”

P2X3 Receptor Ligands: Structural Features and Potential Therapeutic Applications

“…Among them, the 5-cyclohexyl-3-hydroxy-1-(4-(isoxazol-4-yl)phenyl)-4-(4-methoxybenzoyl)-1,5-dihydro-2H-pyrrol-2-one (23) resulted a very potent antagonist of P2X3Rs with an IC 50 of 0.025 μM and a good analgesic efficacy in an acetic acid induced writhing test. Its selectivity was proved respect to 41 receptors and 17 enzymes (Tobinaga et al, 2018).…”