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Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as ?_1A/?_1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile.

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 ?_1A-/?_1D 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 ??-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 ?_1A-/?_1D-adrenoceptor antagonist (K_i(??) = 50 nM, EC₅₀(?_1A) = 0.8 nM, EC₅₀(?_1D) = 1.1 nM), displayed selectivity over ??-adrenoceptors (K_i(??) = 858 nM), and a 5-fold functional preference over the ?_1B subtype. Compound 9 showed adequate metabolic stability in rat-liver microsome assay similar to the reference drug tamsulosin (Cl_int = 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.

SUBMITTER: Canale V

PROVIDER: S-EPMC6225212 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Canale Vittorio V Rak Aleksandra A Kotańska Magdalena M Knutelska Joanna J Siwek Agata A Bednarski Marek M Nowiński Leszek L Zygmunt Małgorzata M Koczurkiewicz Paulina P Pękala Elżbieta E Sapa Jacek J Zajdel Paweł P

Molecules (Basel, Switzerland) 20180829 9

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 t ...[more]

PMID: 30158432

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Project description:We here report the discovery and early characterization of Compound 3, a representative of a novel class of small molecule bradykinin (BK) B2 receptor antagonists, and its superior profile to the prior art B2 receptor antagonists Compound 1 and Compound 2. Compound 3, Compound 2, and Compound 1 are highly potent antagonists of the human recombinant B2 receptor (Kb values 0.24, 0.95, and 1.24 nM, respectively, calcium mobilization assay). Compound 3 is more potent than the prior art compounds and icatibant in this assay (Kb icatibant 2.81 nM). The compounds also potently inhibit BK-induced contraction of endogenous B2 receptors in a human isolated umbilical vein bioassay. The potencies of Compound 3, Compound 2, Compound 1, and icatibant are (pA2 values) 9.67, 9.02, 8.58, and 8.06 (i.e. 0.21, 0.95, 2.63, and 8.71 nM), respectively. Compound 3 and Compound 2 were further characterized. They inhibit BK-induced c-Fos signaling and internalization of recombinant human B2 receptors in HEK293 cells, and do not antagonize the venous effects mediated by other G protein-coupled receptors in the umbilical vein model, including the bradykinin B1 receptor. Antagonist potency of Compound 3 at cloned cynomolgus monkey, dog, rat, and mouse B2 receptors revealed species selectivity, with a high antagonist potency for human and monkey B2 receptors, but several hundred-fold lower potency for the other B2 receptors. The in vitro off-target profile of Compound 3 demonstrates a high degree of selectivity over a wide range of molecular targets, including the bradykinin B1 receptor. Compound 3 showed a lower intrinsic clearance in the microsomal stability assay than the prior art compounds. With an efflux ratio of 1.0 in the Caco-2 permeability assay Compound 3 is predicted to be not a substrate of efflux pumps. In conclusion, we discovered a novel chemical class of highly selective and very potent B2 receptor antagonists, as exemplified by Compound 3. The compound showed excellent absorption in the Caco-2 assay, predictive of good oral bioavailability, and favourable metabolic stability in liver microsomes. Compound 3 has provided a significant stepping stone towards the discovery of the orally bioavailable B2 antagonist PHA-022121, currently in phase 1 clinical development.

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Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as ?_1A/?_1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile.

Publications

Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α<sub>1A</sub>/α<sub>1D</sub>-Adrenergic Receptor Antagonist with Potential Uroselective Profile.

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Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as ?1A/?1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile.

Publications

Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α<sub>1A</sub>/α<sub>1D</sub>-Adrenergic Receptor Antagonist with Potential Uroselective Profile.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as ?_1A/?_1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile.