Discovery of N-[(2S)-5-(6-Fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide, a Novel Clinical AMPA Receptor Positive Modulator

Discovery of N-[(2S)-5-(6-Fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide, a Novel Clinical AMPA Receptor Positive Modulator

A series of AMPA receptor positive allosteric modulators has been optimized from poorly penetrant leads to identify molecules with excellent preclinical pharmacokinetics and CNS penetration. These discoveries led to 17i, a potent, efficacious CNS penetrant molecule with an excellent pharmacokinetic...

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Veröffentlicht in:Journal of medicinal chemistry 2010-08, Vol.53 (15), p.5801-5812
Hauptverfasser: Ward, Simon E, Harries, Mark, Aldegheri, Laura, Andreotti, Daniele, Ballantine, Stuart, Bax, Benjamin D, Harris, Andrew J, Harker, Andy J, Lund, Jesper, Melarange, Rosemary, Mingardi, Anna, Mookherjee, Claudette, Mosley, Julie, Neve, Marta, Oliosi, Beatrice, Profeta, Roberto, Smith, Kathrine J, Smith, Paul W, Spada, Simone, Thewlis, Kevin M, Yusaf, Shahnaz P
Format: Artikel
Sprache:eng
Schlagworte:
Administration, Oral
Allosteric Regulation
Animals
Biological Availability
Blood Proteins - metabolism
Blood-Brain Barrier - metabolism
Callithrix
Cell Line
Crystallography, X-Ray
Dogs
Humans
Indenes - chemical synthesis
Indenes - pharmacokinetics
Indenes - pharmacology
Macaca fascicularis
Male
Microsomes, Liver - metabolism
Models, Molecular
Protein Binding
Protein Structure, Tertiary
Pyridines - chemical synthesis
Pyridines - pharmacokinetics
Pyridines - pharmacology
Rats
Rats, Sprague-Dawley
Receptors, AMPA - physiology
Species Specificity
Stereoisomerism
Structure-Activity Relationship
Sulfonamides - chemical synthesis
Sulfonamides - pharmacokinetics
Sulfonamides - pharmacology
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Zusammenfassung:A series of AMPA receptor positive allosteric modulators has been optimized from poorly penetrant leads to identify molecules with excellent preclinical pharmacokinetics and CNS penetration. These discoveries led to 17i, a potent, efficacious CNS penetrant molecule with an excellent pharmacokinetic profile across preclinical species, which is well tolerated and is also orally bioavailable in humans.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm1005429