Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α1A/α1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile
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 s...
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MDPI AG
2018-08-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/23/9/2175 |
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| author | Vittorio Canale Aleksandra Rak Magdalena Kotańska Joanna Knutelska Agata Siwek Marek Bednarski Leszek Nowiński Małgorzata Zygmunt Paulina Koczurkiewicz Elżbieta Pękala Jacek Sapa Paweł Zajdel |
| author_facet | Vittorio Canale Aleksandra Rak Magdalena Kotańska Joanna Knutelska Agata Siwek Marek Bednarski Leszek Nowiński Małgorzata Zygmunt Paulina Koczurkiewicz Elżbieta Pękala Jacek Sapa Paweł Zajdel |
| author_sort | Vittorio Canale |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T15:26:47Z |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-10T15:26:47Z |
| publishDate | 2018-08-01 |
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| series | Molecules |
| spelling | doaj.art-92168b24298f44cd87e127c4ecdf37932022-12-22T01:43:31ZengMDPI AGMolecules1420-30492018-08-01239217510.3390/molecules23092175molecules23092175Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α1A/α1D-Adrenergic Receptor Antagonist with Potential Uroselective ProfileVittorio Canale0Aleksandra Rak1Magdalena Kotańska2Joanna Knutelska3Agata Siwek4Marek Bednarski5Leszek Nowiński6Małgorzata Zygmunt7Paulina Koczurkiewicz8Elżbieta Pękala9Jacek Sapa10Paweł Zajdel11Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, PolandDepartment of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, PolandDepartment of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, PolandDepartment of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, PolandDepartment of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, PolandDepartment of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, PolandDepartment of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, PolandDepartment of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, PolandDepartment of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, PolandDepartment of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, PolandDepartment of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, PolandDepartment of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, PolandBenign 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.http://www.mdpi.com/1420-3049/23/9/2175arylsulfonamides of alicyclic aminesα1-adrenoceptor antagonistsα1A/B/D receptor selectivitysilodosintamsulosinuroselective activitybenign prostatic hyperplasia |
| spellingShingle | Vittorio Canale Aleksandra Rak Magdalena Kotańska Joanna Knutelska Agata Siwek Marek Bednarski Leszek Nowiński Małgorzata Zygmunt Paulina Koczurkiewicz Elżbieta Pękala Jacek Sapa Paweł Zajdel Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α1A/α1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile Molecules arylsulfonamides of alicyclic amines α1-adrenoceptor antagonists α1A/B/D receptor selectivity silodosin tamsulosin uroselective activity benign prostatic hyperplasia |
| title | Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α1A/α1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile |
| title_full | Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α1A/α1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile |
| title_fullStr | Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α1A/α1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile |
| title_full_unstemmed | Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α1A/α1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile |
| title_short | Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α1A/α1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile |
| title_sort | synthesis and pharmacological evaluation of novel silodosin based arylsulfonamide derivatives as α1a α1d adrenergic receptor antagonist with potential uroselective profile |
| topic | arylsulfonamides of alicyclic amines α1-adrenoceptor antagonists α1A/B/D receptor selectivity silodosin tamsulosin uroselective activity benign prostatic hyperplasia |
| url | http://www.mdpi.com/1420-3049/23/9/2175 |
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