Arylsulfonamide derivatives of (aryloxy)ethyl pyrrolidines and piperidines as a(1)-adrenergic receptor antagonist with uro-selective activity

作者：Rak Aleksandra; C****e Vittorio; Marciniec Krzysztof; Zmudzki Pawel; Kotanska Magdalena; Knutelska Joanna; Siwek Agata; Stachowicz Gabriela; Bednarski Marek^*; Nowinski Leszek; Zygmunt Malgorzata; Zajdel Pawel; Sapa Jacek

来源：Bioorganic & Medicinal Chemistry, 2016, 24(21): 5582-5591.

DOI：10.1016/j.bmc.2016.09.017

• LCAP flexible biomimetic
• Arylsulfonamide derivatives of pyrrolidines and piperidines
• alpha(1)-Adrenoceptors antagonists
• alpha(1A/B) receptor selectivity
• Uroselective activity
• Benign prostatic hyperplasia

A series of arylsulfonamide derivatives of (aryloxy)ethyl pyrrolidines and piperidines was synthesized to develop new alpha(1)-adrenoceptor antagonists with uroselective profile. Biological evaluation for alpha(1)- and alpha(2)-adrenorecepor showed that tested compounds 13-37 displayed high-to-moderate affinity for the ot-radrenoceptor (K-i = 34-348 nM) and moderate selectivity over alpha(2)-receptor subtype. Compounds with highest affinity and selectivity for alpha(1)-radrenoceptor were evaluated in vitro for their intrinsic activity toward alpha(1A)- and alpha(1B)-adrenoceptor subtypes. All compounds behaved as antagonists at both alpha(1)-adrenoceptor subtypes, displaying 2- to 6-fold functional preference to alpha(1A)-subtype. Among them, N-{1-[2-(2-methoxyphenoxy)ethyllpiperidin-4-yl]isoquinoline-4-sulfonamide (25) and 3-chloro-2-fluoro-N-{[1-(2-(2-isopropoxyphenoxy)ethyl)piperidin-4-yl]methyllbenzene sulfonamide (34) displayed the highest preference to alpha(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.

• 出版日期2016-11-1