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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 α7 Nicotinic Acetylcholine Receptor

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Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064
* To whom correspondence should be addressed. Phone: 847-9372972. Fax: 847-9374143. E-mail: [email protected]
Cite this: J. Med. Chem. 2009, 52, 10, 3377–3384
Publication Date (Web):May 6, 2009
https://doi.org/10.1021/jm9003818
Copyright © 2009 American Chemical Society

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    Abstract

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    The discovery of a series of pyrrole-sulfonamides as positive allosteric modulators (PAM) of α7 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 α7 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 α7 nAChRs.

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    LC/MS analyses data for compounds 11 and 19 and hemodynamic evaluation of compound 19 in the rat cardiovascular model. This material is available free of charge via the Internet at http://pubs.acs.org.

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