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.

Autor:	Sinha N; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Karche NP; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Verma MK; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Walunj SS; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Nigade PB; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Jana G; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Kurhade SP; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Hajare AK; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Tilekar AR; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Jadhav GR; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Thube BR; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Shaikh JS; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Balgude S; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Singh LB; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Mahimane V; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Adurkar SK; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Hatnapure G; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Raje F; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Bhosale Y; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Bhanage D; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Sachchidanand S; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Dixit R; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Gupta R; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Bokare AM; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Dandekar M; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Bharne A; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Chatterjee M; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Desai S; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Koul S; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Modi D; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Mehta M; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Patil V; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Singh M; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Gundu J; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Goel RN; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Shah C; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Sharma S; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Bakhle D; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Kamboj RK; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India., Palle VP; Novel Drug Discovery & Development , Lupin Ltd. , Lupin Research Park, Survey No. 46 A/47 A, Village Nande, Taluka Mulshi , Pune 412115 , India.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2020 Feb 13; Vol. 63 (3), pp. 944-960. Date of Electronic Publication: 2019 Dec 06.
DOI:	10.1021/acs.jmedchem.9b01569
Abstrakt:	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.
Databáze:	MEDLINE
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