Discovery of Novel, Potent, Brain-Permeable, and Orally Efficacious Positive Allosteric Modulator of α7 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 thiophenephenyl­sulfonamides
as positive allosteric modulators (PAM) of α7 nicotinic acetylcholine
receptor (α7 nAChR) is described. Optimization of this series
led to identification of compound 28, a novel PAM of
α7 nicotinic acetylcholine receptor (α7 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.