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

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.

Natural Polyhydroxy Flavonoids, Curcuminoids, and Synthetic Curcumin Analogs as α7 nAChRs Positive Allosteric Modulators

“…The α7 acetylcholine nicotinic receptors (α7 nAChRs) are excitatory neurotransmitter receptors of the ligand-gated ion channels superfamily. They are involved in neurological/cognition disorders, as well as in pain and inflammation processes [1][2][3], being potential therapeutic targets for the treatment of several diseases such as Alzheimer or schizophrenia [4][5][6][7]. Therefore, the development of new agents that target these receptors has great therapeutic significance.…”

Recent Advances in the Discovery of Nicotinic Acetylcholine Receptor Allosteric Modulators

“…Furthermore, type II PAMs delay receptor desensitization, reducing the energy barrier. These PAMs can also result in destabilization of the desensitized state of α7 nAChRs, allowing rapid restoration of ion channels in active conformations [ 28 ]. All these pharmacological properties make α7-PAMs ideal candidates for therapeutic uses [ 29 ].…”

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–6

“…Modulation of α7 nicotinic acetylcholine receptors (nAChRs) by positive allosteric modulators (PAM) is a promising therapeutic approach for the treatment of Alzheimer's disease (AD), schizophrenia and attention deficit hyperactivity disorder. Researchers from Lupin LTD have identified a novel PAM of α7 nAChR, a thiophenephenylsulfonamide that showed good in vitro potency, with excellent brain penetration and residence time [44]. This compound reverses the cognitive deficits in episodic/working memory in both time-delay and scopolamine-induced amnesia.…”