3-(Pyridin-2-yl-ethynyl)benzamide metabotropic glutamate receptor 5 negative allosteric modulators: hit to lead studies.
A series of 3-(pyridin-2-yl-ethynyl)benzamide negative allosteric modulators of the metabotropic glutamate receptor 5 (mGluR5 NAMs) have been prepared. Starting from HTS hit 1 (IC(50): 926 nM), potent mGluR5 NAMs showing excellent potencies (IC(50)s<50 nM) and good physicochemical profiles were prepared by monitoring LipE values. One compound 26 showed excellent mGluR5 binding (K(i): 21 nM) and antagonism (IC(50): 8 nM), an excellent rat PK profile (CL: 12 mL/min/kg, %F: 85) and showed oral activity in a mouse 4-Plate Behavioral model of anxiety (MED: 30 mpk) and a mouse Stress Induced Hyperthermia model of anxiety (MED 17.8 mpk).
Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA. adam.gilbert@pfizer.com
Adam M
AM
Gilbert
Matthew G
MG
Bursavich
Sabrina
S
Lombardi
Adedayo
A
Adedoyin
Jason M
JM
Dwyer
Zoe
Z
Hughes
Jeffrey C
JC
Kern
Xavier
X
Khawaja
Sharon
S
Rosenzweig-Lipson
William J
WJ
Moore
Sarah J
SJ
Neal
Michael
M
Olsen
Stacey J Sukoff
SJ
Rizzo
Dane
D
Springer
D000494:Allosteric Regulation; D000818:Animals; D001008:Anxiety Disorders / Q000188:drug therapy; D001549:Benzamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004195:Disease Models, Animal; D057166:High-Throughput Screening Assays; D051379:Mice; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry* / Q000378:metabolism
D001549:Benzamides; C578936:Grm5 protein, mouse; C578937:Grm5 protein, rat; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C037689:benzamide