Structure–activity relationships of novel non-competitive mGluR1 antagonists: A potential treatment for chronic pain

Weakly active ( 4) was converted into low molecular weight, high activity ( 29) using library chemistry. A series of novel mGluR1 antagonists have been prepared. Incorporation of fragments derived from weak lead matter into a library led to enhanced potency in a new chemical series. A chemistry driv...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2007-01, Vol.17 (2), p.486-490
Main Authors: Owen, Dafydd R., Dodd, Peter G., Gayton, Simon, Greener, Ben S., Harbottle, Gareth W., Mantell, Simon J., Maw, Graham N., Osborne, Simon A., Rees, Huw, Ringer, Tracy J., Rodriguez-Lens, Margarita, Smith, Graham F.
Format: Article
Language:English
Subjects:
Analgesics
Animals
Binding, Competitive - drug effects
Biological and medical sciences
c log P
Chemical Phenomena
Chemistry, Physical
CHO Cells
Chronic Disease
Chronic pain
CNS
Cricetinae
Cricetulus
Dose-Response Relationship, Drug
Glutamatergic system (aspartate and other excitatory aminoacids)
Glutamic Acid - pharmacology
Library
log D
Medical sciences
Metabolism
mGluR
mGluR1
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pain - drug therapy
Pharmacology. Drug treatments
Pyrazine
Pyrazines - chemical synthesis
Pyrazines - pharmacology
Quinoxaline
Rats
Receptors, Metabotropic Glutamate - antagonists & inhibitors
Structure-Activity Relationship
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Summary:Weakly active ( 4) was converted into low molecular weight, high activity ( 29) using library chemistry. A series of novel mGluR1 antagonists have been prepared. Incorporation of fragments derived from weak lead matter into a library led to enhanced potency in a new chemical series. A chemistry driven second library iteration, covering a greatly enhanced area of chemical space, maintained good potency and introduced metabolic stability.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2006.10.015