molecules Article Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α1A/α1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile Vittorio Canale 1, Aleksandra Rak 2, Magdalena Kota ´nska 2, Joanna Knutelska 2, Agata Siwek 3, Marek Bednarski 2, Leszek Nowi ´nski 2, Małgorzata Zygmunt 2, Paulina Koczurkiewicz 4, Elzbieta˙ P˛ekala 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; [email protected] (V.C.); [email protected] (P.Z.) 2 Department of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland; [email protected] (A.R.); [email protected] (M.K.); [email protected] (J.K.); [email protected] (M.B.); [email protected] (L.N.); [email protected] (M.Z.) 3 Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland; [email protected] 4 Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland; [email protected] (P.K.); [email protected] (E.P.) * Correspondence: [email protected] Received: 12 July 2018; Accepted: 13 August 2018; Published: 29 August 2018 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. Keywords: arylsulfonamides of alicyclic amines; α1-adrenoceptor antagonists; α1A/B/D receptor selectivity; silodosin; tamsulosin; uroselective activity; benign prostatic hyperplasia 1. Introduction α1-Adrenergic receptors (α1-ARs) belong to the G-protein-coupled receptor superfamily. They generally mediate their actions through Gq/11 proteins, which stimulate the activation of phospholipase C, via generation of the inositol triphosphate and diacylglycerol, liberation of calcium from the endoplasmic reticulum, and/or activation of genes. To date, three subtypes of α1-AR, i.e., α1A, Molecules 2018, 23, 2175; doi:10.3390/molecules23092175 www.mdpi.com/journal/molecules Molecules 2018, 23, 2175 2 of 17 α1B, and α1D have been identified in human tissues [1]. Although these subtypes display high structural homology, they differ in biological structure, tissue distributions, and pharmacological actions [2]. 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 systemMolecules 2018 [3]., 23α, 1x -ARs play an important role in the pathogenesis of hypertension2 of and17 benign prostatic hyperplasia (BPH) [4,5]. α1A, α1B, and α1D have been identified in human tissues [1]. Although these subtypes display high An increased α1-adrenergic prostate smooth muscle tone together with enhanced prostate structural homology, they differ in biological structure, tissue distributions, and pharmacological volume are recognized causes of the disease [6]. BPH clinically manifests with lower urinary actions [2]. Several studies revealed that α1-AR subtypes are highly expressed in blood vessels— tract symptomsmainly α (LUTS)1B-ARs, inas the storage urogenital (irritative) area (prostat symptomse, urethra, bladder, (nocturia, ureter)—mainly urgency, α1A incontinence, and α1D-ARs, altered bladder sensations,and central nervous increased system frequency) [3]. α1-ARs or play obstructive an important (voiding) role in the symptoms pathogenesis (hesitancy,of hypertension slow stream, intermittency,and benign splitting, prostatic straining, hyperplasia terminal (BPH) [4,5]. dribble) [7]. Some of them commonly occur secondary An increased α1-adrenergic prostate smooth muscle tone together with enhanced prostate to obstructivevolume symptoms, are recognized and causes result of fromthe disease exaggerated, [6]. BPH clinically spontaneous manifests detrusorwith lower contractions urinary tract (known as bladdersymptoms overactivity) (LUTS) [ as7, 8storage]. BPH (irritative) affects symptoms the majority (nocturia, of men urgency, with incontinence, increasing altered frequency bladder as they get older [9]. LUTS,sensations, if left increased untreated, frequency) result inor significantobstructive impairment(voiding) symptoms of quality (hesitancy, of life andslow leadstream, to long-term complications,intermittency, such as splitting, recurrent straining, urinary terminal tract dribbl infectionse) [7]. Some or renal of them insufficiency commonly occur [10 secondary]. to obstructive symptoms, and result from exaggerated, spontaneous detrusor contractions (known as α Despitebladder several overactivity) classes of[7,8]. BPH BPH medications affects the majority available, of men studies with increasing have shown frequency that as 1they-adrenolitics get are consideredolder as the [9]. first-lineLUTS, if left drug untreated, treatment result [in11 significant]. It has beenimpairment suggested of quality that of enhanced, life and lead three-to-nine-fold to long- greater expressionterm complications, of α1A -such and as αrecurrent1D-ARs urinary in an tract enlarged infections prostate or renal insufficiency and bladder [10]. neck, comparing to Despite several classes of BPH medications available, studies have shown that α1-adrenolitics healthy tissue, remains in strong contribution with LUTS occurrence [12]. Consequently, an α1A- and are considered as the first-line drug treatment [11]. It has been suggested that enhanced, three-to- α -AR blockade relieves obstructive and voiding symptoms by relaxation of the smooth muscle in 1D nine-fold greater expression of α1A- and α1D-ARs in an enlarged prostate and bladder neck, comparing the prostateto healthy and bladder tissue, remains detrusor, in strong respectively contributi [on13 with]. LUTS occurrence [12]. Consequently, an α1A- In contrast,and α1D-AR a blockadeblockade relieves of α 1Bobstructive-ARs, which and voiding are predominantlysymptoms by relaxation expressed of the smooth in vascular muscle smooth muscle [14in], the results prostate in and vasodilation bladder detrusor, of blood respectively vessels [13]. leading to cardiovascular side effects, especially In contrast, a blockade of α1B-ARs, which are predominantly expressed in vascular smooth α orthostaticmuscle hypotension [14], results [15 in]. vasodilation The old of1-adrenolitics, blood vessels leading bearing to cardiovascular quinazoline side scaffold, effects, especially i.e., doxazosin or terazosin,orthostatic display nonspecific hypotension [15]. interaction The old α1 with-adrenolitics, all α1-AR bearing subtypes quinazoline [5]. scaffold, On the i.e., other doxazosin hand, or naftopidil, tamsulosin,terazosin, and silodosin display nonspecific (Figure1 interaction), displaying with all relatively α1-AR subtypes high [5].α1A On- andthe otherα1D -ARhand, subtypenaftopidil, selectivity, effectivelytamsulosin, relieve symptoms and silodosin related (Figure to 1), BHP/LUTS displaying relatively disease high without α1A- and undesirable α1D-AR subtype side selectivity, effects on blood effectively relieve symptoms related to BHP/LUTS disease without undesirable side effects on blood pressure [16pressure–18]. [16–18]. Figure 1. Chemical structures of selective α1A- and α1D-AR antagonists. Figure 1. Chemical structures of selective α1A- and α1D-AR antagonists. Integrating a concept of arylpiperazine biomimetics recently adapted for development of Integratingselective a conceptand potent of 5-HT arylpiperazine7R antagonists biomimetics [19], we explored recently the adaptedcommon forchemical development space with of selective tamsulosin to propose modifications leading to increased α1A-AR properties. Associating and potent 5-HT R antagonists [19], we explored the common chemical space with tamsulosin arylsulfonamide7 and aryloxylalkyl fragments identified compound I, which behaved as an α1A-AR to proposeantagonist modifications and displayed leading a moderate to increased selectivityα receptor1A-AR properties.profile over α1B-AR Associating subtype [20]. arylsulfonamide In an and aryloxylalkylattempt to fragmentsfurther increase identified