Low brain penetrant CB1 receptor agonists for the treatment of neuropathic pain

Novel, low brain penetrant, orally bioavailable CB1 receptor agonists were designed using calculated polar surface area as a predictor of CNS permeability. This approach led to the discovery of LBP1, an orally bioavailable, low brain penetrant CB1 receptor agonist with robust activity in rodent mode...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2012-04, Vol.22 (8), p.2932-2937
Main Authors: Adam, Julia M., Clark, John K., Davies, Keneth, Everett, Kathryn, Fields, Ruth, Francis, Stuart, Jeremiah, Fiona, Kiyoi, Takao, Maidment, Maurice, Morrison, Angus, Ratcliffe, Paul, Prosser, Alan, Schulz, Jurgen, Wishart, Grant, Baker, James, Boyce, Susan, Campbell, Robert, Cottney, Jean E., Deehan, Maureen, Martin, Iain
Format: Article
Language:English
Subjects:
agonists
animal models
Animals
Biological and medical sciences
brain
Brain - blood supply
Brain - metabolism
Caco-2 Cells
Cannabinoid
CB1
Drug addictions
Drug Design
Humans
Indoles - chemical synthesis
Indoles - chemistry
Indoles - pharmacokinetics
Medical sciences
Mice
Neuralgia - drug therapy
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Oxadiazoles - chemical synthesis
Oxadiazoles - chemistry
Oxadiazoles - pharmacokinetics
pain
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Peripherally restricted
Pharmacology. Drug treatments
Rats
Receptor, Cannabinoid, CB1 - agonists
receptors
surface area
Toxicology
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Summary:Novel, low brain penetrant, orally bioavailable CB1 receptor agonists were designed using calculated polar surface area as a predictor of CNS permeability. This approach led to the discovery of LBP1, an orally bioavailable, low brain penetrant CB1 receptor agonist with robust activity in rodent models of neuropathic pain and a good preclinical therapeutic profile. Novel, low brain penetrant, orally bioavailable CB1 receptor agonists were designed starting from a mature lead series of potent brain penetrant CB1 receptor agonists. Increasing the calculated polar surface area was found to be a good strategy for reducing brain penetration whilst retaining drug-like properties. This in silico approach led to the discovery of LBP1, an orally bioavailable, low brain penetrant CB1 receptor agonist with robust activity in rodent models of neuropathic pain and a good preclinical therapeutic profile, which was selected for clinical development.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.02.048