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1. 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.

Author

Sinha N, Karche NP, Verma MK, Walunj SS, Nigade PB, Jana G, Kurhade SP, Hajare AK, Tilekar AR, Jadhav GR, Thube BR, Shaikh JS, Balgude S, Singh LB, Mahimane V, Adurkar SK, Hatnapure G, Raje F, Bhosale Y, Bhanage D, Sachchidanand S, Dixit R, Gupta R, Bokare AM, Dandekar M, Bharne A, Chatterjee M, Desai S, Koul S, Modi D, Mehta M, Patil V, Singh M, Gundu J, Goel RN, Shah C, Sharma S, Bakhle D, Kamboj RK, and Palle VP

Subjects
Alzheimer Disease drug therapy, Animals, Brain metabolism, Clinical Trials as Topic, Drug Stability, Humans, Male, Molecular Structure, Nicotinic Agonists chemical synthesis, Nicotinic Agonists pharmacokinetics, Nootropic Agents chemical synthesis, Nootropic Agents pharmacokinetics, Rats, Sprague-Dawley, Rats, Wistar, Structure-Activity Relationship, Sulfonamides chemical synthesis, Sulfonamides pharmacokinetics, Thiophenes chemical synthesis, Thiophenes pharmacokinetics, Drug Discovery, Nicotinic Agonists pharmacology, Nootropic Agents pharmacology, Sulfonamides pharmacology, Thiophenes pharmacology, alpha7 Nicotinic Acetylcholine Receptor agonists
Abstract

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.

Published
2020
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