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.
Highlights
Benign prostatic hyperplasia (BPH) is the most common male clinical problem impacting the quality of life of older men
[19], fragments we explored thecompound commonI, which chemical space tamsulosin arylsulfonamide and aryloxylalkyl identified behaved as anwith α1A-AR
2-(2,2,2-trifluoroethoxy)phenoxy fragment of silodosin with an alicyclic amine core functionalized with arylsulfonamide moiety, derived from previously reported compound
Summary
Benign prostatic hyperplasia (BPH) is the most common male clinical problem impacting the quality of life of older men. Compound 9 did not decrease systolic and diastolic blood pressure in normotensive anesthetized rats in the dose of 2 mg/kg, i.v. 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. Several studies revealed that α1 -AR subtypes are highly expressed in blood vessels—mainly α1B -ARs, in the urogenital area (prostate, urethra, bladder, ureter)—mainly α1A and α1D -ARs, and central nervous system [3]. Α1-ARsor play an important role in thesymptoms pathogenesis(hesitancy, of hypertension bladder sensations, increased frequency) obstructive (voiding) slow stream, and benign prostatic hyperplasia (BPH) [4,5]. BPH clinically manifests detrusor with lowercontractions urinary tract (known as bladdersymptoms overactivity)
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