Discovery of selective N-[3-(1-methyl-piperidine-4-carbonyl)-phenyl]-benzamide-based 5-HT1F receptor agonists: Evolution from bicyclic to monocyclic cores

Article abstract of DOI:10.1016/j.bmcl.2015.07.042

Preclinical experiments and clinical observations suggest the potential effectiveness of selective 5-HT_1F receptor agonists in migraine. Identifying compounds with enhanced selectivity is crucial to assess its therapeutic value. Replacement of the indole nucleus in 2 (LY334370) with a monocyclic phenyl ketone moiety generated potent and more selective 5-HT_1F receptor agonists. Focused SAR studies around this central phenyl ring demonstrated that the electrostatic and steric interactions of the substituent with both the amide CONH group and the ketone C=O group play pivotal roles in affecting the adopted conformation and thus the 5-HT_1F receptor selectivity. Computational studies confirmed the observed results and provide a useful tool in the understanding of the conformational requirements for 5-HT_1F receptor agonist activity and selectivity. Through this effort, the 2-F-phenyl and N-2-pyridyl series were also identified as potent and selective 5-HT_1F receptor agonists.