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

被引：19

作者：

Sinha, Neelima ^{[1
]}

Karche, Navnath P. ^{[1
]}

Verma, Mahip Kalyan ^{[1
]}

Walunj, Sameer S. ^{[1
]}

Nigade, Prashant B. ^{[1
]}

Jana, Gourhari ^{[1
]}

Kurhade, Sanjay P. ^{[1
]}

Hajare, Anil K. ^{[1
]}

Tilekar, Ajay R. ^{[1
]}

Jadhav, Ganesh R. ^{[1
]}

Thube, Baban R. ^{[1
]}

Shaikh, Javed S. ^{[1
]}

Balgude, Sudhakar ^{[1
]}

Singh, Lairikyengbam Bikramjit ^{[1
]}

Mahimane, Vijaya ^{[1
]}

Adurkar, Shridhar K. ^{[1
]}

Hatnapure, Girish ^{[1
]}

Raje, Firoj ^{[1
]}

Bhosale, Yogesh ^{[1
]}

Bhanage, Dnyaneshwar ^{[1
]}

Sachchidanand, Sachchidanand ^{[1
]}

Dixit, Ruchi ^{[1
]}

Gupta, Rajesh ^{[1
]}

Bokare, Anand M. ^{[1
]}

Dandekar, Manoj ^{[1
]}

Bharne, Ashish ^{[1
]}

Chatterjee, Manavi ^{[1
]}

Desai, Sagar ^{[1
]}

Koul, Sarita ^{[1
]}

Modi, Dipak ^{[1
]}

Mehta, Maneesh ^{[1
]}

Patil, Vinod ^{[1
]}

Singh, Minakshi ^{[1
]}

Gundu, Jayasagar ^{[1
]}

Goel, Rajan N. ^{[1
]}

Shah, Chirag ^{[1
]}

Sharma, Sharad ^{[1
]}

Bakhle, Dhananjay ^{[1
]}

Kamboj, Rajender Kumar ^{[1
]}

Palle, Venkata P. ^{[1
]}

机构：

[1] Lupin Ltd, Lupin Res Pk, Novel Drug Discovery & Dev, Survey 46 A-47 A, Pune 412115, Maharashtra, India

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 03期

关键词：

COGNITIVE IMPAIRMENT; PARTIAL AGONIST; SCHIZOPHRENIA; TRANSMISSION; SELECTIVITY; ACTIVATION; EVP-6124; RODENTS; SAFETY; MEMORY;

D O I：

10.1021/acs.jmedchem.9b01569

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery of a series of thiophenephenyl-sulfonamides as positive allosteric modulators (PAM) of alpha 7 nicotinic acetylcholine receptor (alpha 7 nAChR) is described. Optimization of this series led to identification of compound 28, a novel PAM of alpha 7 nicotinic acetylcholine receptor (alpha 7 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.

引用

页码：944 / 960

页数：17

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