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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- 作者：Ramin Faghih ; Sujatha M. Gopalakrishnan ; Jens Halvard Gronlien ; John Malysz ; Clark A. Briggs ; Caroline Wetterstrand ; Hilde Ween ; Michael P. Curtis ; Kathy A. Sarris ; Gregory A. Gfesser ; Rachid El-Kouhe
- 刊名：Journal of Medicinal Chemistry
- 出版年：2009
- 出版时间：May 28, 2009
- 年：2009
- 卷：52
- 期：10
- 页码：3377-3384
- 全文大小：191K
- 年卷期：v.52,no.10(May 28, 2009)
- ISSN：1520-4804
文摘
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.