Synthesis and SAR of N-Chlorophenyl Substituted Piperazinylethyl-aminomethylpyrazoles as 5-HT3A Inhibitors

Abstract

he 5-HT3A receptors are one of ligand-gated ion channels and are known to be involved in visceral pain, anxiety, or anticancer agent-induced nausea and vomiting. In present study, we designed novel skeletons based on the developed 5-HT3 receptor antagonists and evaluated their effects on 5-HT3A receptor channel currents (I5-IIT) of a series of pyrazole derivatives having N-chlorophenylpiperazine functionality (6-9). We found that most N-p-chlorophenyl substituted piperazinyl-pyrazole derivatives (7b, 7c, 7e, and 7h) exhibited the high potency for the inhibition of I-5-HT,I- whereas the compound without (6) or with m-chlorophenyl group ( a serious of 8 and 9) showed the low potency. These results indicate that p-chlorophenyl group is might play an important role for increasing the inhibitory potency on I5-IIT.