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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

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journal contribution
posted on 06.12.2019 by Neelima Sinha, Navnath P. Karche, Mahip Kalyan Verma, Sameer S. Walunj, Prashant B. Nigade, Gourhari Jana, Sanjay P. Kurhade, Anil K. Hajare, Ajay R. Tilekar, Ganesh R. Jadhav, Baban R. Thube, Javed S. Shaikh, Sudhakar Balgude, Lairikyengbam Bikramjit Singh, Vijaya Mahimane, Shridhar K. Adurkar, Girish Hatnapure, Firoj Raje, Yogesh Bhosale, Dnyaneshwar Bhanage, Sachchidanand Sachchidanand, Ruchi Dixit, Rajesh Gupta, Anand M. Bokare, Manoj Dandekar, Ashish Bharne, Manavi Chatterjee, Sagar Desai, Sarita Koul, Dipak Modi, Maneesh Mehta, Vinod Patil, Minakshi Singh, Jayasagar Gundu, Rajan N. Goel, Chirag Shah, Sharad Sharma, Dhananjay Bakhle, Rajender Kumar Kamboj, Venkata P. Palle
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.