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Molecules
Volume 23
Issue 9
10.3390/molecules23092175
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Article

Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α1A/α1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile

by
Vittorio Canale
1,
Aleksandra Rak
2,
Magdalena Kotańska
2,
Joanna Knutelska
2,
Agata Siwek
3,
Marek Bednarski
2,
Leszek Nowiński
2,
Małgorzata Zygmunt
2,
Paulina Koczurkiewicz
4,
Elżbieta Pękala
4,
Jacek Sapa
2,* and
Paweł Zajdel
1
1
Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
2
Department of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
3
Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
4
Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
*
Author to whom correspondence should be addressed.
Molecules 2018, 23(9), 2175; https://doi.org/10.3390/molecules23092175
Received: 12 July 2018 / Revised: 3 August 2018 / Accepted: 13 August 2018 / Published: 29 August 2018
(This article belongs to the Section Medicinal Chemistry)
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Abstract

Benign prostatic hyperplasia (BPH) is the most common male clinical problem impacting the quality of life of older men. Clinical studies have indicated that the inhibition of α1A-/α1D adrenoceptors might offer effective therapy in lower urinary tract symptoms. Herein, a limited series of arylsulfonamide derivatives of (aryloxy)ethyl alicyclic amines was designed, synthesized, and biologically evaluated as potent α1-adrenoceptor antagonists with uroselective profile. Among them, compound 9 (3-chloro-2-fluoro-N-([1-(2-(2-(2,2,2-trifluoroethoxy)phenoxy]ethyl)piperidin-4-yl)methyl)benzenesulfonamide) behaved as an α1A-/α1D-adrenoceptor antagonist (Ki(α1) = 50 nM, EC50(α1A) = 0.8 nM, EC50(α1D) = 1.1 nM), displayed selectivity over α2-adrenoceptors (Ki(α2) = 858 nM), and a 5-fold functional preference over the α1B subtype. Compound 9 showed adequate metabolic stability in rat-liver microsome assay similar to the reference drug tamsulosin (Clint = 67 and 41 µL/min/mg, respectively). Compound 9 did not decrease systolic and diastolic blood pressure in normotensive anesthetized rats in the dose of 2 mg/kg, i.v. These data support development of uroselective agents in the group of arylsulfonamides of alicyclic amines with potential efficacy in the treatment of lower urinary tract symptoms associated to benign prostatic hyperplasia. View Full-Text
Keywords: arylsulfonamides of alicyclic amines; α1-adrenoceptor antagonists; α1A/B/D receptor selectivity; silodosin; tamsulosin; uroselective activity; benign prostatic hyperplasia arylsulfonamides of alicyclic amines; α1-adrenoceptor antagonists; α1A/B/D receptor selectivity; silodosin; tamsulosin; uroselective activity; benign prostatic hyperplasia
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MDPI and ACS Style

Canale, V.; Rak, A.; Kotańska, M.; Knutelska, J.; Siwek, A.; Bednarski, M.; Nowiński, L.; Zygmunt, M.; Koczurkiewicz, P.; Pękala, E.; Sapa, J.; Zajdel, P. Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α1A/α1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile. Molecules 2018, 23, 2175. https://doi.org/10.3390/molecules23092175

AMA Style

Canale V, Rak A, Kotańska M, Knutelska J, Siwek A, Bednarski M, Nowiński L, Zygmunt M, Koczurkiewicz P, Pękala E, Sapa J, Zajdel P. Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α1A/α1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile. Molecules. 2018; 23(9):2175. https://doi.org/10.3390/molecules23092175

Chicago/Turabian Style

Canale, Vittorio, Aleksandra Rak, Magdalena Kotańska, Joanna Knutelska, Agata Siwek, Marek Bednarski, Leszek Nowiński, Małgorzata Zygmunt, Paulina Koczurkiewicz, Elżbieta Pękala, Jacek Sapa, and Paweł Zajdel. 2018. "Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α1A/α1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile" Molecules 23, no. 9: 2175. https://doi.org/10.3390/molecules23092175

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