3-(Piperazinylpropyl)indoles: selective, orally bioavailable h5-HT1D receptor agonists as potential antimigraine agents.
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.
Chambers
M S
MS
Department of Chemistry, Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K.
Street
L J
LJ
Goodacre
S
S
Hobbs
S C
SC
Hunt
P
P
Jelley
R A
RA
Matassa
V G
VG
Reeve
A J
AJ
Sternfeld
F
F
Beer
M S
MS
Stanton
J A
JA
Rathbone
D
D
Watt
A P
AP
MacLeod
A M
AM
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D006224:Cricetinae; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008881:Migraine Disorders / Q000188:drug therapy*; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
C117663:1-(3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl)-4-(2-(3-fluorophenyl)ethyl)piperazine; D007211:Indoles; D010879:Piperazines; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D017366:Serotonin Receptor Agonists