Acylglycinamides as inhibitors of glycine transporter type 1

A screening hit was used as the basis for the core structure of a new series of acylglycinamide GlyT-1 inhibitors. Investigation of the SAR around four areas of diversity used facile chemistry to prepare compounds quickly. By focussing on reducing the lipophilicity and improving the aqueous solubili...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2011-10, Vol.21 (20), p.6176-6179
Main Authors: Blunt, Richard, Porter, Roderick, Johns, Amanda, Nash, David, Puckey, Gemma, Wyman, Paul, Herdon, Hugh, Teague, Simon, Hadden, Victoria, Fontana, Stefano, Gordon, Laurie
Format: Article
Language:English
Subjects:
Acylglycinamides
Animals
bioavailability
Biological and medical sciences
Glycine - analogs & derivatives
Glycine - chemistry
Glycine - metabolism
Glycine - pharmacokinetics
Glycine - pharmacology
Glycine Plasma Membrane Transport Proteins - antagonists & inhibitors
Glycine Plasma Membrane Transport Proteins - metabolism
Glycine transporter type 1
GlyT-1
Humans
hydrophobicity
Inhibitory Concentration 50
Medical sciences
Neuropharmacology
Pharmacology. Drug treatments
Psycholeptics: tranquillizer, neuroleptic
Psychology. Psychoanalysis. Psychiatry
Psychopharmacology
Rats
SAR
Schizophrenia
screening
Solubility
Structure-Activity Relationship
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Summary:A screening hit was used as the basis for the core structure of a new series of acylglycinamide GlyT-1 inhibitors. Investigation of the SAR around four areas of diversity used facile chemistry to prepare compounds quickly. By focussing on reducing the lipophilicity and improving the aqueous solubility in the series we were able to prepare a compound ( 17e) with a good level of activity at GlyT-1, selectivity over GlyT-2 and moderate oral bioavailability.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.07.096