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

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...

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Published in:Journal of medicinal chemistry Vol. 63; no. 3; pp. 944 - 960
Main Authors: Sinha, Neelima, Karche, Navnath P, Verma, Mahip Kalyan, Walunj, Sameer S, Nigade, Prashant B, Jana, Gourhari, Kurhade, Sanjay P, Hajare, Anil K, Tilekar, Ajay R, Jadhav, Ganesh R, Thube, Baban R, Shaikh, Javed S, Balgude, Sudhakar, Singh, Lairikyengbam Bikramjit, Mahimane, Vijaya, Adurkar, Shridhar K, Hatnapure, Girish, Raje, Firoj, Bhosale, Yogesh, Bhanage, Dnyaneshwar, Sachchidanand, Sachchidanand, Dixit, Ruchi, Gupta, Rajesh, Bokare, Anand M, Dandekar, Manoj, Bharne, Ashish, Chatterjee, Manavi, Desai, Sagar, Koul, Sarita, Modi, Dipak, Mehta, Maneesh, Patil, Vinod, Singh, Minakshi, Gundu, Jayasagar, Goel, Rajan N, Shah, Chirag, Sharma, Sharad, Bakhle, Dhananjay, Kamboj, Rajender Kumar, Palle, Venkata P
Format: Journal Article
Language:English
Published: United States American Chemical Society 13-02-2020
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Summary: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.
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ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.9b01569