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3-(Pyridin-2-yl-ethynyl)benzamide metabotropic glutamate receptor 5 negative allosteric modulators: hit to lead studies.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2011 Jan 01; Vol. 21 (1), pp. 195-9. Date of Electronic Publication: 2010 Nov 12. - Publication Year :
- 2011
-
Abstract
- 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).<br /> (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Subjects :
- Allosteric Regulation
Animals
Anxiety Disorders drug therapy
Benzamides pharmacokinetics
Benzamides therapeutic use
Disease Models, Animal
High-Throughput Screening Assays
Mice
Pyridines pharmacokinetics
Pyridines therapeutic use
Rats
Receptor, Metabotropic Glutamate 5
Receptors, Metabotropic Glutamate metabolism
Benzamides chemistry
Pyridines chemistry
Receptors, Metabotropic Glutamate chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 21
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 21126874
- Full Text :
- https://doi.org/10.1016/j.bmcl.2010.11.038