Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α1A/α1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile
Abstract
:1. Introduction
2. Chemistry
3. In Vitro Experiments
3.1. Radioligand Binding and Functional Evaluation
3.2. Metabolic Stability
4. In Vivo Pharmacology
5. Results and Discussion
6. Conclusions
7. Experimental
7.1. Chemistry
7.1.1. General Chemical Methods
7.1.2. Preparation of 1-Methoxy-2-(2,2,2-trifluoroethoxy)benzene (2)
7.1.3. Preparation of 2-(2,2,2-Trifluoroethoxy)phenol (3)
7.1.4. Preparation of 1-(2-Bromoethoxy)-2-(2,2,2-trifluoroethoxy)benzene (4)
7.1.5. General Procedure for the Alkylation of Boc-Protected Amines (5–7)
tert-Butyl ((1-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)piperidin-4-yl)methyl)carbamate (5)
tert-Butyl (R)-(1-{2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}pyrrolidin-3-yl)carbamate (6)
tert-Butyl (S)-(1-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)pyrrolidin-3-yl)carbamate (7)
7.1.6. General Procedure for Preparation of Final Compounds (8–18)
4-Fluoro-N-[(1-{2-[(2,2,2-trifluoroethoxy)phenoxy]ethyl}piperidin-4-yl)methyl]benzenesulfonamide (8)
3-Chloro-2-fluoro-N-[(1-{2-[(2,2,2-trifluoroethoxy)phenoxy]ethyl}piperidin-4-yl)methyl]benzenesulfonamide (9)
5-Chloro-2-fluoro-N-[(1-{2-[(2,2,2-trifluoroethoxy)phenoxy]ethyl}piperidin-4-yl)methyl]benzenesulfonamide (10)
5-Chloro-2-methoxy-N-[(1-{2-[(2,2,2-trifluoroethoxy)phenoxy]ethyl}piperidin-4-yl)methyl]benzenesulfonamide (11)
3,4-Dimethoxy-N-[(1-{2-[(2,2,2-trifluoroethoxy)phenoxy]ethyl}piperidin-4-yl)methyl]benzenesulfonamide (12)
(R)-4-Fluoro-N-(1-{2-[(2,2,2-trifluoroethoxy)phenoxy]ethyl}pyrrolidin-3-yl)benzenesulfonamide (13)
(S)-4-Fluoro-N-(1-{2-[(2,2,2-trifluoroethoxy)phenoxy]ethyl}pyrrolidin-3-yl)benzenesulfonamide (14)
(R)-5-Chloro-2-fluoro-N-(1-{2-[(2,2,2-trifluoroethoxy)phenoxy]ethyl}pyrrolidin-3-yl)benzenesulfonamide (15)
(S)-5-Chloro-2-fluoro-N-(1-{2-[(2,2,2-trifluoroethoxy)phenoxy]ethyl}pyrrolidin-3-yl)benzenesulfonamide (16)
(R)-3,4-Dimethoxy-N-(1-{2-[(2,2,2-trifluoroethoxy)phenoxy]ethyl}pyrrolidin-3-yl)benzenesulfonamide (17)
(S)-3,4-Dimethoxy-N-(1-{2-[(2,2,2-trifluoroethoxy)phenoxy]ethyl}pyrrolidin-3-yl)benzenesulfonamide (18)
7.2. In Vitro Pharmacology
7.2.1. Determination of the Affinity of the Tested Compounds at the α1- and α2-ARs
7.2.2. Determination of the Affinity of the Tested Compounds at the 5-HT1A and 5-HT7Rs
7.2.3. Determination of the Intrinsic Activity of the α1A-ARs
7.2.4. Determination of the Intrinsic Activity of the α1B-ARs and α1D-ARs
7.2.5. Determination of In Vitro Metabolic Stability
7.3. In Vivo Pharmacology
7.3.1. Animals
7.3.2. Determination of the Effect of the Tested Compounds on Blood Pressure after a Single Administration in Rats
7.3.3. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Sample Availability: Samples of the compounds 2–18 are available from the authors. |
Compd. | R1 | Enant | n | m | R | Ki [nM] a ± SEM | ||
---|---|---|---|---|---|---|---|---|
α1 | α2 | Sα2/α1 b | ||||||
Ic | 3-Cl,2-F | - | 1 | 1 | Isopropyl | 71 ± 4 | 1212 ± 99 | 17 |
8 | 4-F | - | 1 | 1 | TFE d | 20 ± 2 | 919 ± 25 | 46 |
9 | 3-Cl,2-F | - | 1 | 1 | TFE | 50 ± 2 | 858 ± 69 | 17 |
10 | 5-Cl,2-F | - | 1 | 1 | TFE | 26 ± 1 | 579 ± 20 | 23 |
11 | 5-Cl,2-OMe | - | 1 | 1 | TFE | 95 ± 3 | 1092 ± 62 | 12 |
12 | 3,4-diOMe | - | 1 | 1 | TFE | 19 ± 3 | 524 ± 31 | 27 |
IIc | 5-Cl,2-F | S | 0 | 0 | Isopropyl | 242 ± 16 | >10,000 | >41 |
13 | 4-F | R | 0 | 0 | TFE | 188 ± 3 | 1687 ± 85 | 9 |
14 | 4-F | S | 0 | 0 | TFE | 134 ± 16 | >10,000 | >70 |
15 | 5-Cl,2-F | R | 0 | 0 | TFE | 171 ± 4 | 1188 ± 74 | 7 |
16 | 5-Cl,2-F | S | 0 | 0 | TFE | 117 ± 10 | 1466 ± 80 | 13 |
17 | 3,4-diOMe | R | 0 | 0 | TFE | 105 ± 7 | 435 ± 21 | 4 |
18 | 3,4-diOMe | S | 0 | 0 | TFE | 70 ± 1 | 1141 ± 42 | 16 |
Compd. | α1A | α1B | α1D | |||
---|---|---|---|---|---|---|
IC50 [nM] a | Profile | IC50 [nM] a | Profile | IC50 [nM] a | Profile | |
Ic | 11.1 | ANT b | 42.1 | ANT | 15.1 | ANT |
8 | 3.8 | ANT | 8.3 | ANT | 1.1 | ANT |
9 | 0.8 | ANT | 3.9 | ANT | 1.1 | ANT |
10 | 2.1 | ANT | 10.1 | ANT | 2.7 | ANT |
12 | 15.0 | ANT | 0.02 | ANT | 2.6 | ANT |
tamsulosin | 0.07 | ANT | 1.3 | ANT | 0.005 | ANT |
terazosin | 51.9 | ANT | 1.7 | ANT | 0.2 | ANT |
phenylephrine | 56.0 (EC50) | AGO b | 0.9 (EC50) | AGO | 12.1 (EC50) | AGO |
Compd. | 5-HT1A | 5-HT7 |
---|---|---|
Ki [nM] a ± SEM | %inh @ 10−6/10−7 M | |
9 | 70 ± 3.5 | 93/57 |
10 | 46 ± 0.6 | 94/61 |
Compd. | t½ [min] | Clint [μL/min/mg] | Major Metabolic Pathway |
---|---|---|---|
I | 40 | 87 | N-dealkylation |
9 | 51.5 | 67 | N-dealkylation |
10 | 37.8 | 91.7 | N-dealkylation |
Tamsulosin | 83 | 41 | N-dealkylation |
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Canale, V.; Rak, A.; Kotańska, M.; Knutelska, J.; Siwek, A.; Bednarski, M.; Nowiński, L.; Zygmunt, M.; Koczurkiewicz, P.; Pękala, E.; et al. 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
Canale V, Rak A, Kotańska M, Knutelska J, Siwek A, Bednarski M, Nowiński L, Zygmunt M, Koczurkiewicz P, Pękala E, et al. 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 StyleCanale, Vittorio, Aleksandra Rak, Magdalena Kotańska, Joanna Knutelska, Agata Siwek, Marek Bednarski, Leszek Nowiński, Małgorzata Zygmunt, Paulina Koczurkiewicz, Elżbieta Pękala, and et al. 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