Discovery of 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744) as a novel positive allosteric modulator of the alpha7 nicotinic acetylcholine receptor

The discovery of a series of pyrrole-sulfonamides as positive allosteric modulators (PAM) of alpha7 nAChRs is described. Optimization of this series led to the identification of 19 (A-867744), a novel type II PAM with good potency and selectivity. Compound 19 showed acceptable pharmacokinetic profil...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2009-05, Vol.52 (10), p.3377
Main Authors: Faghih, Ramin, Gopalakrishnan, Sujatha M, Gronlien, Jens Halvard, Malysz, John, Briggs, Clark A, Wetterstrand, Caroline, Ween, Hilde, Curtis, Michael P, Sarris, Kathy A, Gfesser, Gregory A, El-Kouhen, Rachid, Robb, Holly M, Radek, Richard J, Marsh, Kennan C, Bunnelle, William H, Gopalakrishnan, Murali
Format: Article
Language:English
Subjects:
Allosteric Regulation
alpha7 Nicotinic Acetylcholine Receptor
Animals
Benzenesulfonamides
Brain - metabolism
Cells, Cultured
Drug Discovery
Mice
Microsomes
Oocytes
Patch-Clamp Techniques
Pharmacokinetics
Pyrroles - pharmacology
Receptors, Nicotinic - drug effects
Sensory Gating - drug effects
Sulfonamides - pharmacology
Xenopus laevis
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Summary:The discovery of a series of pyrrole-sulfonamides as positive allosteric modulators (PAM) of alpha7 nAChRs is described. Optimization of this series led to the identification of 19 (A-867744), a novel type II PAM with good potency and selectivity. Compound 19 showed acceptable pharmacokinetic profile across species and brain levels sufficient to modulate alpha7 nAChRs. In a rodent model of sensory gating, 19 normalized gating deficits. These results suggest that 19 represents a novel class of molecules capable of allosteric modulation of the alpha7 nAChRs.
ISSN:1520-4804
DOI:10.1021/jm9003818