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

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 19showed acceptable pharmacokinetic profile across species and brain levels sufficient to modulate α7 nAChRs. In a rodent model of sensory gating, 19normalized gating deficits. These results suggest that 19represents a novel class of molecules capable of allosteric modulationof the α7 nAChRs.