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

M S Chambers; L J Street; S Goodacre; S C Hobbs; P Hunt; R A Jelley; V G Matassa; A J Reeve; F Sternfeld; M S Beer; J A Stanton; D Rathbone; A P Watt; A M MacLeod

doi:10.1021/jm980569z

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

J Med Chem. 1999 Feb 25;42(4):691-705. doi: 10.1021/jm980569z.

Authors

M S Chambers¹, L J Street, S Goodacre, S C Hobbs, P Hunt, R A Jelley, V G Matassa, A J Reeve, F Sternfeld, M S Beer, J A Stanton, D Rathbone, A P Watt, A M MacLeod

Affiliation

¹ Department of Chemistry, Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K.

PMID: 10052976
DOI: 10.1021/jm980569z

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.

MeSH terms

Administration, Oral
Animals
Biological Availability
CHO Cells
Cricetinae
Indoles / chemical synthesis*
Indoles / chemistry
Indoles / metabolism
Indoles / pharmacology
Male
Migraine Disorders / drug therapy*
Models, Molecular
Piperazines / chemical synthesis*
Piperazines / chemistry
Piperazines / metabolism
Piperazines / pharmacology
Radioligand Assay
Rats
Rats, Sprague-Dawley
Receptor, Serotonin, 5-HT1B
Receptor, Serotonin, 5-HT1D
Receptors, Serotonin / drug effects*
Receptors, Serotonin / metabolism
Recombinant Proteins / agonists
Recombinant Proteins / metabolism
Serotonin Receptor Agonists / chemical synthesis*
Serotonin Receptor Agonists / chemistry
Serotonin Receptor Agonists / metabolism
Serotonin Receptor Agonists / pharmacology
Structure-Activity Relationship

Substances

1-(3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl)-4-(2-(3-fluorophenyl)ethyl)piperazine
Indoles
Piperazines
Receptor, Serotonin, 5-HT1B
Receptor, Serotonin, 5-HT1D
Receptors, Serotonin
Recombinant Proteins
Serotonin Receptor Agonists