Arylsulfonamide derivatives of (aryloxy)ethyl pyrrolidines and piperidines as α1-adrenergic receptor antagonist with uro-selective activity.

Bioorganic & medicinal chemistry 2016 Nov 01

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A series of arylsulfonamide derivatives of (aryloxy)ethyl pyrrolidines and piperidines was synthesized to develop new α1-adrenoceptor antagonists with uroselective profile. Biological evaluation for α1- and α2-adrenorecepor showed that tested compounds 13-37 displayed high-to-moderate affinity for the α1-adrenoceptor (Ki=34-348nM) and moderate selectivity over α2-receptor subtype. Compounds with highest affinity and selectivity for α1-adrenoceptor were evaluated in vitro for their intrinsic activity toward α1A- and α1B-adrenoceptor subtypes. All compounds behaved as antagonists at both α1-adrenoceptor subtypes, displaying 2- to 6-fold functional preference to α1A-subtype. Among them, N-{1-[2-(2-methoxyphenoxy)ethyl]piperidin-4-yl}isoquinoline-4-sulfonamide (25) and 3-chloro-2-fluoro-N-{[1-(2-(2-isopropoxyphenoxy)ethyl)piperidin-4-yl]methyl}benzene sulfonamide (34) displayed the highest preference to α1A-adrenoceptor. Finally, compounds 25 and 34 (2-5mg/kg, iv), in contrast to tamsulosin (1-2mg/kg, iv), did not significantly decrease systolic and diastolic blood pressure in normotensive anesthetized rats to determine their influence on blood pressure. Copyright © 2016 Elsevier Ltd. All rights reserved.

Citation

Aleksandra Rak, Vittorio Canale, Krzysztof Marciniec, Paweł Żmudzki, Magdalena Kotańska, Joanna Knutelska, Agata Siwek, Gabriela Stachowicz, Marek Bednarski, Leszek Nowiński, Małgorzata Zygmunt, Paweł Zajdel, Jacek Sapa. Arylsulfonamide derivatives of (aryloxy)ethyl pyrrolidines and piperidines as α1-adrenergic receptor antagonist with uro-selective activity. Bioorganic & medicinal chemistry. 2016 Nov 01;24(21):5582-5591