3-(Piperazinylpropyl)indoles:  Selective, Orally Bioavailable h5-HT1D Receptor
Agonists as Potential Antimigraine Agents

Chambers, Mark S.; Street, Leslie J.; Goodacre, Simon; Hobbs, Sarah C.; Hunt, Peter; Jelley, Richard A.; Matassa, Victor G.; Reeve, Austin J.; Sternfeld, Francine; Beer, Margaret S.; Stanton, Josephine A.; Rathbone, Denise; Watt, Alan P.; MacLeod, Angus M.

doi:10.1021/jm980569z.s001

jm980569z_si_001.pdf (30.85 kB)

3-(Piperazinylpropyl)indoles: Selective, Orally Bioavailable h5-HT_1D Receptor Agonists as Potential Antimigraine Agents

journal contribution

posted on 1999-02-03, 00:00 authored by Mark S. Chambers, Leslie J. Street, Simon Goodacre, Sarah C. Hobbs, Peter Hunt, Richard A. Jelley, Victor G. Matassa, Austin J. Reeve, Francine Sternfeld, Margaret S. Beer, Josephine A. Stanton, Denise Rathbone, Alan P. Watt, Angus M. MacLeod

Clinically effective antimigraine drugs such as Sumatriptan have similar affinity at h5-HT_1D and h5-HT_1B receptors. In the search for a h5-HT_1D-selective agonist as an antimigraine agent, a novel series of 3-(propylpiperazinyl)indoles have been synthesized and evaluated at h5-HT_1D and h5-HT_1B receptors. This class of compounds has provided subnanomolar, fully efficacious h5-HT_1D agonists with up to 200-fold selectivity for the h5-HT_1D receptor over the h5-HT_1B receptor. Unlike other h5-HT_1D-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)piperazine (7f) which has excellent selectivity for h5-HT_1D 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.