Discovery and biological profile of 4-(1-aryltriazol-4-yl)-tetrahydropyridines as an orally active new class of metabotropic glutamate receptor 1 antagonist.
We describe here the discovery and the structure-activity relationship (SAR) of a series of 4-(1-Aryltriazol-4-yl)-tetrahydropyridines as novel mGluR1 antagonists. Our extensive chemical modification of lead compound 2 successfully led to fluoropyridine analogs 7j and 1 with improved in vivo antagonistic activities. Among the evaluated compounds, chemically stable urea analog 1 showed oral antagonistic activity at dose ranges of 10-30mg/kg in an animal model.
Tsukuba Research Institute, Banyu Pharmaceutical CO., LTD, 3 Okubo, Tsukuba 300-2611, Japan. satoru_ito@merck.com
Satoru
S
Ito
Atsushi
A
Satoh
Yasushi
Y
Nagatomi
Yukari
Y
Hirata
Gentaroh
G
Suzuki
Toshifumi
T
Kimura
Akio
A
Satow
Shunsuke
S
Maehara
Hirohiko
H
Hikichi
Mikiko
M
Hata
Hiroshi
H
Kawamoto
Hisashi
H
Ohta
D000284:Administration, Oral; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1