A novel series of positive modulators of the AMPA receptor: Discovery and structure based hit-to-lead studies

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 19; pp. 5753 - 5756
• Main Authors: Jamieson, Craig, Basten, Stephanie, Campbell, Robert A., Cumming, Iain A., Gillen, Kevin J., Gillespie, Jonathan, Kazemier, Bert, Kiczun, Michael, Lamont, Yvonne, Lyons, Amanda J., Maclean, John K.F., Moir, Elizabeth M., Morrow, John A., Papakosta, Marianthi, Rankovic, Zoran, Smith, Lynn
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.10.2010; Elsevier
• Subjects: Allosteric modulator; Allosteric Regulation; AMPA receptor; Animals; Binding Sites; Biological and medical sciences; Crystallography, X-Ray; Drug Design; Drug Evaluation, Preclinical; Glutamatergic system (aspartate and other excitatory aminoacids); High-Throughput Screening Assays; Hit-to-lead; Humans; Indazoles - chemical synthesis; Indazoles - chemistry; Indazoles - pharmacology; Medical sciences; Microsomes - metabolism; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Protein Structure, Tertiary; Rats; Receptors, AMPA - chemistry; Receptors, AMPA - metabolism; SBDD; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology; SBDD; AMPA receptor; Allosteric modulator; Hit-to-lead; Human; Cell permeability; Molecular structure; Glutamate receptor; X ray diffraction; Indazole derivatives; Biological activity; Pyrrolidine derivatives; Benzothiophene derivatives; Metabolic stability; Cell line; Allosteric regulation; Modulation; Colon; Fluorine Organic compounds; Chemical synthesis; Crystalline structure
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.07.138

Starting from an HTS hit, the evolution of lead compound 22, a positive allosteric modulator of the AMPA receptor is described using structure based drug design. Starting from an HTS derived hit 1, application of biostructural data facilitated rapid optimization to lead 22, a novel AMPA receptor modulator. This is the first demonstration of how structure based drug design can be exploited in an optimization program for a glutamate receptor.