A novel series of positive modulators of the AMPA receptor: Structure-based lead optimization

The identification of an advanced lead compound 5 guided by structure based drug design is described. Starting from lead compound 1, we demonstrate how X-ray structural data can be used to understand SAR and expediently optimize bioavailability in a novel series of AMPA receptor modulators, furnishi...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2010-10, Vol.20 (20), p.6072-6075
Hauptverfasser:	Jamieson, Craig, Campbell, Robert A., Cumming, Iain A., Gillen, Kevin J., Gillespie, Jonathan, Kazemier, Bert, Kiczun, Michael, Lamont, Yvonne, Lyons, Amanda J., Maclean, John K.F., Martin, Frederic, Moir, Elizabeth M., Morrow, John A., Pantling, John, Rankovic, Zoran, Smith, Lynn
Format:	Artikel
Sprache:	eng
Schlagworte:	Allosteric Regulation Amines - chemical synthesis Amines - chemistry Amines - pharmacokinetics Amines - pharmacology AMPA receptor Animals Bioavailability Biological and medical sciences Biological Availability Crystallography, X-Ray Drug Design Glutamatergic system (aspartate and other excitatory aminoacids) Humans Ion channels Medical sciences Models, Molecular Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Positive allosteric modulators Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - pharmacokinetics Pyrazoles - pharmacology Rats Rats, Wistar Receptors, AMPA - chemistry Receptors, AMPA - metabolism SBDD Stereoisomerism Structure-Activity Relationship
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Zusammenfassung:	The identification of an advanced lead compound 5 guided by structure based drug design is described. Starting from lead compound 1, we demonstrate how X-ray structural data can be used to understand SAR and expediently optimize bioavailability in a novel series of AMPA receptor modulators, furnishing 5 with improved bioavailability and robust in vivo activity.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.08.063