1-(3-(5-(1-2-4-triazol-4-yl)-1h-indol-3-yl)propyl)-4-(2-(3-fluorophenyl)ethyl)piperazine and Migraine-Disorders

Clinically effective antimigraine drugs such as Sumatriptan have similar affinity at h5-HT1D and h5-HT1B receptors. In the search for a h5-HT1D-selective agonist as an antimigraine agent, a novel series of 3-(propylpiperazinyl)indoles have been synthesized and evaluated at h5-HT1D and h5-HT1B receptors. This class of compounds has provided subnanomolar, fully efficacious h5-HT1D agonists with up to 200-fold selectivity for the h5-HT1D receptor over the h5-HT1B receptor. Unlike other h5-HT1D-selective series, several propylpiperazines demonstrate good oral bioavailability. The optimum compound was 1-(3-[5-(1,2, 4-triazol-4-yl)-1H-indol-3-yl]propyl)-4-(2-(3-fluorophenyl)ethyl)p ipe razine (7f) which has excellent selectivity for h5-HT1D receptors over other 5-HT receptor subtypes and good oral bioavailability in three species. Compound 7f has been selected for further investigation as a potential development candidate in the treatment of migraine.

Topics: Administration, Oral; Animals; Biological Availability; CHO Cells; Cricetinae; Indoles; Male; Migraine Disorders; Models, Molecular; Piperazines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Recombinant Proteins; Serotonin Receptor Agonists; Structure-Activity Relationship

Topics: Administration, Oral; Animals; Biological Availability; Migraine Disorders; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Serotonin Receptor Agonists; Species Specificity