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

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• 作者：Aleksandra Rak^a ; Vittorio Canale^b ; Krzysztof Marciniec^c ; Paweł Żmudzki^b ; Magdalena Kotańska^a ; Joanna Knutelska^a ; Agata Siwek^e ; Gabriela Stachowicz^e ; Marek Bednarski^a ; ^{marek.bednarski@uj.edu.pl" class="auth_mail" title="E-mail the corresponding author} ; Leszek Nowiński^d ; Małgorzata Zygmunt^a ; Paweł Zajdel^b ; Jacek Sapa^a
• 关键词：LCAP flexible biomimetic ; Arylsulfonamide derivatives of pyrrolidines and piperidines ; α1-Adrenoceptors antagonists ; α1A/B receptor selectivity ; Uroselective activity ; Benign prostatic hyperplasia
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 November 2016
• 年：2016
• 卷：24
• 期：21
• 页码：5582-5591
• 全文大小：667 K

文摘

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 (K_i = 34–348 nM) 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 α_1A- and α_1B-adrenoceptor subtypes. All compounds behaved as antagonists at both α₁-adrenoceptor subtypes, displaying 2- to 6-fold functional preference to α_1A-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 α_1A-adrenoceptor. Finally, compounds 25 and 34 (2–5 mg/kg, iv), in contrast to tamsulosin (1–2 mg/kg, iv), did not significantly decrease systolic and diastolic blood pressure in normotensive anesthetized rats to determine their influence on blood pressure.