3-(piperazinylpropyl)indoles: Selective, orally bioavailable h5-HT1D receptor agonists as potential antimigraine agents

Clinically effective antimigraine drugs such as Sumatriptan have similar af finity at h5-HT1D and h5-HT1B receptors. In the search for a h5-HT1D-select ive agonist as an antimigraine agent, a novel series of 3-(propylpiperaziny l)indoles have been synthesized and evaluated at h5-HT1D and h5-HT1B recept ors. This class of compounds has provided subnanomolar, fully efficacious h 5-HT1D agonists with up to 200-fold selectivity for the h5-HT1D receptor ov er the h5-HT1B receptor. Unlike other h5-HT1D-selective series, several pro pylpiperazines demonstrate good oral bioavailability. The optimum compound was 1-(3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]-4-(2-(3-fluorophenyl)ethyl) piperazine (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 de velopment candidate in the treatment of migraine.