3-(Piperazinylpropyl)indoles: selective, orally bioavailable h5-HT1D receptor agonists as potential antimigraine agents.

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Chambers MS, Street LJ, Goodacre S, Hobbs SC, Hunt P, Jelley RA, Matassa VG, Reeve AJ, Sternfeld F, Beer MS, Stanton JA, Rathbone D, Watt AP, MacLeod AM

3-(Piperazinylpropyl)indoles: selective, orally bioavailable h5-HT1D receptor agonists as potential antimigraine agents.

J Med Chem. 1999 Feb 25;42(4):691-705.

PubMed ID
10052976 [ View in PubMed
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Abstract

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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
Sumatriptan5-hydroxytryptamine receptor 1BIC 50 (nM)11N/AN/ADetails
Sumatriptan5-hydroxytryptamine receptor 1DEC 50 (nM)14N/AN/ADetails
Sumatriptan5-hydroxytryptamine receptor 1DIC 50 (nM)6.7N/AN/ADetails