5-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-2,3'-bipyridine: a highly potent, orally active metabotropic glutamate subtype 5 (mGlu5) receptor antagonist with anxiolytic activity.
Structure-activity relationship studies leading to the discovery of a new, orally active mGlu5 receptor antagonist are described. The title compound, 5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-2,3'-bipyridine, is highly potent in vitro, has good in vivo receptor occupancy, and is efficacious in the rat fear-potentiated startle model of anxiety following oral dosing.
Roppe
Jeffrey R
JR
Department of Medicinal Chemistry, Merck Research Laboratories, San Diego, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA. jeffrey_roppe@merck.com
Wang
Bowei
B
Huang
Dehua
D
Tehrani
Lida
L
Kamenecka
Theodore
T
Schweiger
Edwin J
EJ
Anderson
Jeffery J
JJ
Brodkin
Jesse
J
Jiang
Xiaohui
X
Cramer
Merryl
M
Chung
Janice
J
Reyes-Manalo
Grace
G
Munoz
Benito
B
Cosford
Nicholas D P
ND
D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001007:Anxiety; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008958:Models, Molecular; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000502:physiology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
D014151:Anti-Anxiety Agents; D018691:Excitatory Amino Acid Antagonists; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles