N-[3-(2-Dimethylaminoethyl)-2-methyl-1H- indol-5-yl]-4-fluorobenzamide: a potent, selective, and orally active 5-HT(1F) receptor agonist potentially useful for migraine therapy.
Recent studies have demonstrated that selective 5-HT(1F) receptor agonists inhibit neurogenic dural inflammation, a model of migraine headache, indicating that these compounds may be effective therapies for the treatment of migraine pain. This communication describes the synthesis and discovery of a novel compound, N-[3-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl]-4-fluorobenzamide (4), which possesses high binding affinity and selectivity at the 5-HT(1F) receptor relative to more than 40 other serotonergic and nonserotonergic receptors examined.
Xu
Y C
YC
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. Xu_Yao-Chang@Lilly.com
Johnson
K W
KW
Phebus
L A
LA
Cohen
M
M
Nelson
D L
DL
Schenck
K
K
Walker
C D
CD
Fritz
J E
JE
Kaldor
S W
SW
LeTourneau
M E
ME
Murff
R E
RE
Zgombick
J M
JM
Calligaro
D O
DO
Audia
J E
JE
Schaus
J M
JM
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D004388:Dura Mater / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007249:Inflammation; D008881:Migraine Disorders / Q000188:drug therapy*; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D051381:Rats; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012501:Saphenous Vein / Q000187:drug effects / Q000502:physiology; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000096642:Receptor, Serotonin, 5-HT1F
D001549:Benzamides; D007211:Indoles; D017981:Receptors, Neurotransmitter; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D000096642:Receptor, Serotonin, 5-HT1F; C440613:N-(3-(2-dimethylaminoethyl)-2-methyl-1H-indol-5-yl)-4-fluorobenzamide