3-(Piperazinylpropyl)indoles:  Selective, Orally Bioavailable h5-HT<sub>1D</sub> Receptor Agonists as Potential Antimigraine Agents

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