Discovery of novel, potent, brain-permeable and orally efficacious positive allosteric modulator of alpha 7 nicotinic acetylcholine receptor [4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide], structure activity relationship and preclinical characterization.

The discovery of a series of thiophenephenyl-sulfonamides as positive allosteric modulators (PAM) of alpha 7 nicotinic acetylcholine receptor (alpha 7 nAChR) is described. Optimization of this series led to identification of compound 28, a novel PAM of alpha 7 nicotinic acetylcholine receptor (alpha 7 nAChR). Compound 28 showed good in vitro potency, with pharmacokinetic profile across species with excellent brain penetration and residence time. Compound 28 robustly reversed the cognitive deficits in episodic/working memory in both time-delay and scopolamine-induced amnesia paradigms in the novel object and social recognition tasks, at very low dose levels. Additionally, compound 28 has shown excellent safety profile in phase 1 clinical trials and is being evaluated for efficacy and safety as monotherapy in patients with mild to moderate Alzheimer's disease.