Three novel series of α-aminoamides derivatives were designed and synthesized based on ralfinamide,and their Nav1.7 inhibitory activities were evaluated using manual patch clamp electrophysiology. Active compounds in...Three novel series of α-aminoamides derivatives were designed and synthesized based on ralfinamide,and their Nav1.7 inhibitory activities were evaluated using manual patch clamp electrophysiology. Active compounds inhibited Nav1.7 with half maximal inhibitory concentration(IC_(50)) values ranging from2.9 μmol/L to 21.4 μmol/L. Among them, the most potent compound 19h exhibited about 12-fold potency better than ralfinamide. The investigation of their structure-activity relationship gives a strategy to improve the Nav1.7 inhibition of ralfinamide analogues. Compound 19h was efficacious in antinociception in the mouse spared nerve injury(SNI) model of neuropathic pain without causing sedation in the open field test.展开更多
Many therapeutic drugs are racemates;i.e. they are chiral molecules consisting of “left”- and “right-handed” enantiomers (stereoisomers that are mirror images of each other, and are non-superimposable). In some ca...Many therapeutic drugs are racemates;i.e. they are chiral molecules consisting of “left”- and “right-handed” enantiomers (stereoisomers that are mirror images of each other, and are non-superimposable). In some cases, both enantiomers of the drug contribute to some extent (or equally) to the therapeutic effect;in other cases they contribute not at all. The same is true for the adverse effects of racemate drugs: the adverse effects of a racemate drug can be greater-than, less-than, or equal to one or the other enantiomer. An unusual situation arises when a drug consists of “atropisomers”, stereoisomers arising because of hindered rotation about a single chemical bond. We summarize the concept of atropisomerism, and give examples.展开更多
基金Financial supports by National Natural Science Foundation of China (Nos. 82003565 and 81973162)the Science and Technology Commission of Shanghai Municipality (No. 20S11902300,China)。
文摘Three novel series of α-aminoamides derivatives were designed and synthesized based on ralfinamide,and their Nav1.7 inhibitory activities were evaluated using manual patch clamp electrophysiology. Active compounds inhibited Nav1.7 with half maximal inhibitory concentration(IC_(50)) values ranging from2.9 μmol/L to 21.4 μmol/L. Among them, the most potent compound 19h exhibited about 12-fold potency better than ralfinamide. The investigation of their structure-activity relationship gives a strategy to improve the Nav1.7 inhibition of ralfinamide analogues. Compound 19h was efficacious in antinociception in the mouse spared nerve injury(SNI) model of neuropathic pain without causing sedation in the open field test.
文摘Many therapeutic drugs are racemates;i.e. they are chiral molecules consisting of “left”- and “right-handed” enantiomers (stereoisomers that are mirror images of each other, and are non-superimposable). In some cases, both enantiomers of the drug contribute to some extent (or equally) to the therapeutic effect;in other cases they contribute not at all. The same is true for the adverse effects of racemate drugs: the adverse effects of a racemate drug can be greater-than, less-than, or equal to one or the other enantiomer. An unusual situation arises when a drug consists of “atropisomers”, stereoisomers arising because of hindered rotation about a single chemical bond. We summarize the concept of atropisomerism, and give examples.
