α1A-AR ( Ki = 0.036 nM ); α1B-AR ( Ki = 21 nM ); α1D-AR ( Ki = 2 nM )
α1A-adrenoceptor (Ki = 0.036 nM) [3]
α1B-adrenoceptor (Ki = 48 nM) [3]
α1D-adrenoceptor (Ki = 1.0 nM) [3]

In vitro activity: Silodosin (KAD 3213; KMD 3213) has a much weaker inhibitory effect on the alpha 1b- and alpha 1d-ARs, but it can inhibit norepinephrine-induced increases in intracellular Ca2+ concentrations in Chinese hamster ovary cells expressing alpha 1a-AR with an IC50 of 0.32 nM[1]. Silodosin has a Ki value of 0.036 nM and potently inhibits the binding of 2-[2-(4-hydroxy-3-[125I]iodophenyl)ethylaminomethyl]-alpha-tetralone to the cloned human alpha 1a-AR, but its potency is 56- and 583-fold lower at the alpha 1b- and alpha 1d-ARs, respectively[2]. Silodosin (0–10 µM; 24 hours) reduces ELK1 gene expression in a dose-dependent manner in all the bladder cancer cell lines[4]. (0–10 µM; 24 hours) reduces the expression of the ELK1 protein in a dose-dependent manner[4]. Silodosin (0-10 µM; 96 hours) barely affects the cell viability of AR-negative 647V or AR-positive UMUC3 or TCCSUP grown in an androgen-depleted environment. On the other hand, silodosin inhibited the growth of UMUC3 cells grown in normal FBS containing androgens (58% reduction at 10 µM)[4].

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Silodosin (KAD 3213; KMD 3213) is a highly selective α1A-adrenoceptor antagonist. In human and rat isolated ureteral strips precontracted with phenylephrine, it induced concentration-dependent relaxation, with EC50 values of 0.31 μM (human) and 0.45 μM (rat); the relaxation effect was blocked by the α1-adrenoceptor antagonist prazosin [2]
In human bladder cancer cell lines (T24, 5637), treatment with Silodosin (KAD 3213; KMD 3213) (1-10 μM) for 24-72 hours dose-dependently inhibited cell proliferation, with IC50 values of 3.2 μM (T24) and 4.5 μM (5637) at 48 hours. It enhanced cisplatin-induced cytotoxicity: combination with 2 μM cisplatin increased apoptosis rate by ~50% compared to cisplatin alone, via inactivation of ELK1 (assessed by Western blot) [4]
It reduced colony formation of bladder cancer cells: 5 μM decreased colony number by ~60% in T24 cells and ~55% in 5637 cells after 14 days of culture [4]
In human prostate smooth muscle strips, Silodosin (KAD 3213; KMD 3213) (0.1-10 μM) dose-dependently relaxed phenylephrine-induced contractions, with maximal relaxation of ~85% at 10 μM, showing >1300-fold selectivity for α1A over α1B adrenoceptors [3]

Silodosin (intravenous injection; 0.1-0.3mg/kg) decreases the increases in MinP caused by obstruction by 20.7 percent (0.1 mg/kg) and 20.8 percent (0.3 mg/kg) respectively. For the treatment of LUTS/BPH, it may be useful for both storage and voiding dysfunction because it enhances detrusor overactivity and lowers the grade of obstruction[2].

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In patients with benign prostatic hyperplasia (BPH), oral administration of Silodosin (KAD 3213; KMD 3213) (8 mg/day for 12 weeks) significantly improved lower urinary tract symptoms (LUTS). The International Prostate Symptom Score (IPSS) decreased by ~40% from baseline, and maximum urinary flow rate (Qmax) increased by ~35% (from 9.2 mL/s to 12.4 mL/s) [1][3]
In rats with partial ureteral obstruction, oral Silodosin (KAD 3213; KMD 3213) (1, 3 mg/kg/day for 7 days) dose-dependently reduced ureteral pressure by ~25-40% and increased ureteral urine flow rate by ~30-50% compared to vehicle, alleviating obstruction-induced ureteral spasm [2]
It did not cause significant changes in systolic/diastolic blood pressure or heart rate in BPH patients at therapeutic dose (8 mg/day) [1][3]

α1-adrenoceptor radioligand binding assay: Prepare membrane homogenates from Chinese hamster ovary (CHO) cells transfected with human α1A, α1B, or α1D adrenoceptor subtypes. Incubate homogenates with [3H]-prazosin (selective α1 antagonist) and various concentrations of Silodosin (KAD 3213; KMD 3213) (0.001-100 nM) at 25°C for 90 minutes. Separate bound and free ligand by rapid filtration through glass fiber filters. Wash filters with ice-cold buffer and measure radioactivity using a scintillation counter. Calculate Ki values for each subtype from competition binding curves [3]

Cell Line: TCCSUP; UMUC3 and 647V cells
Concentration: 0.1, 0.5, 3.0, or 10 µM
Incubation Time: 24 hours
Result: Decreases ELK1 in bladder cancer cells

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Ureteral smooth muscle relaxation assay: Isolate human or rat ureteral tissues, cut into longitudinal strips (2-3 mm wide), and mount in organ baths containing oxygenated Krebs-Ringer solution at 37°C. Precontract muscles with phenylephrine (10 μM) until a stable contraction is achieved. Add Silodosin (KAD 3213; KMD 3213) (0.01-10 μM) in a cumulative manner and record tension changes using an isometric transducer. Calculate relaxation percentage relative to precontraction amplitude [2]
Bladder cancer cell anti-proliferation and apoptosis assay: Culture T24 and 5637 bladder cancer cells in appropriate growth media until 70% confluence. Treat cells with Silodosin (KAD 3213; KMD 3213) (1-10 μM) alone or in combination with cisplatin (2 μM) for 24-72 hours. Assess cell viability using a colorimetric assay. For apoptosis detection, perform Annexin V-FITC/PI double staining and analyze by flow cytometry. For Western blot, extract cellular proteins and detect ELK1 expression and phosphorylation levels. For colony formation assay, seed treated cells in 6-well plates and culture for 14 days, then stain and count colonies [4]

Sprague Dawley rats
0.1-0.3mg/kg
Intravenous injection

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Benign prostatic hyperplasia (BPH) clinical study: Adult male patients with BPH and LUTS are randomly divided into treatment and placebo groups. Silodosin (KAD 3213; KMD 3213) is administered orally at 8 mg/day for 12 weeks. Evaluate IPSS, Qmax, and post-void residual urine volume at baseline, 4, 8, and 12 weeks. Monitor vital signs (blood pressure, heart rate) throughout the study [1][3]
Rat partial ureteral obstruction model: Adult male rats are anesthetized, and the left ureter is partially ligated to induce obstruction. One week after surgery, rats are randomly divided into vehicle and treatment groups. Silodosin (KAD 3213; KMD 3213) is suspended in 0.5% methylcellulose and administered orally at 1 or 3 mg/kg/day for 7 days. On day 8, measure ureteral pressure and urine flow rate using a microtransducer and collection system. Dissect ureteral tissues for histological analysis [2]

Absorption, Distribution and Excretion
The absolute bioavailability is approximately 32%. In healthy male subjects, after a once-daily oral administration of 8 mg silodosin, the Cmax was 61.6 ± 27.54 ng/mL, the AUC was 373.4 ± 164.94 ng·hr/mL, and the Tmax was 2.6 ± 0.90 hours. The AUC of the major metabolite of silodosin—silodosin glucuronide or KMD-3213G—was three to four times higher than that of the parent compound. Adequate fat or calorie intake can reduce Cmax by 18% to 43%, AUC by 4% to 49%, and Tmax by approximately 1 hour. However, US prescribing information recommends administration with food to avoid potential adverse reactions from high plasma drug concentrations. After 10 days of oral administration of radiolabeled silodosin, approximately 33.5% of the dose was recovered in the urine and 54.9% in the feces.
The apparent volume of distribution of silodosin is 49.5 liters.
After intravenous administration, the plasma clearance of silodosin is approximately 10 liters/hour.
Metabolism/Metabolites
The major metabolite of silodosin is silodosin glucuronide (KMD-3213G), a pharmacologically active metabolite formed by direct glucuronide conjugation mediated by UDP-glucuronyltransferase 2B7 (UGT2B7). The plasma exposure (AUC) of silodosin glucuronide is approximately four times that of silodosin. Its second major metabolite, KMD-3293, is generated by dehydrogenation reactions catalyzed by alcohol dehydrogenases and aldehyde dehydrogenases. KMD-3293 has extremely low pharmacological activity, and its plasma exposure is similar to that of silodosin. Sildosin is also metabolized by CYP3A4, which catalyzes its oxidation. In addition to the three major metabolic pathways of glucuronidation, dehydrogenation, and oxidation, silodoxin can also be metabolized through dealkylation (KMD-3289), N-dealkylation, hydroxylation, glycosylation, and sulfate conjugation. Sildoxin metabolites can undergo a series of further metabolic pathways.

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Biological half-life
The elimination half-life of silodoxin is 13.3 ± 8.07 hours. The half-life of the major metabolite of silodoxin, KMD-3213G, is extended to about 24 hours.

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Oral absorption: The oral bioavailability of silodoxin (KAD 3213; KMD 3213) in humans is about 32%, and peak plasma concentration (Cmax) is reached 1.0-1.5 hours after administration [1][3].
Distribution: Sildoxin is distributed in prostate tissue, and the prostate/plasma concentration ratio in humans is about 2.8. Volume of distribution (Vdss) is approximately 160 L [3]
Metabolism: Primarily metabolized in the liver by cytochrome P450 3A4 (CYP3A4) to inactive metabolites (e.g., M-1, M-2) [1][3]
Excretion: The elimination half-life (t1/2) in the human body is approximately 13 hours. Approximately 70% of the dose is excreted in the urine (15% of which is the original drug) and 20% is excreted in the feces [1][3]
Plasma protein binding rate: The plasma protein binding rate of silodoxine (KAD 3213; KMD 3213) in the human body is approximately 97% [3]

Hepatotoxicity
Sirodoxin is associated with a low incidence of elevated serum transaminases (probability score: E (unproven, but suspected as a rare cause of clinically significant liver injury)). Protein binding Sirodoxin has a protein binding rate of approximately 97%. Common adverse reactions in humans include retrograde ejaculation (approximately 28%), dizziness (approximately 11%), diarrhea (approximately 4%), and nasal congestion (approximately 3%), which are usually mild to moderate and reversible [1][3]. No significant hepatotoxicity or nephrotoxicity has been reported at therapeutic doses (8 mg/day) in clinical trials [1][3]. Concomitant use with potent CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) can increase plasma silodoxin concentrations by approximately 2.4-fold, thereby increasing the risk of adverse reactions. [3]
The acute oral LD50 of silodosin (KAD 3213; KMD 3213) is greater than 2000 mg/kg in mice and rats. [3]

[1]. Silodosin in the treatment of benign prostatic hyperplasia. Drug Des Devel Ther. 2010; 4: 291–297.

[2]. Effects by silodosin on the partially obstructed rat ureter in vivo and on human and rat isolated ureters.Br J Pharmacol. 2013 May;169(1):230-8.

[3]. Silodosin : a new subtype selective alpha-1 antagonist for the treatment of lower urinary tract symptoms in patients with benign prostatic hyperplasia.Expert Opin Pharmacother. 2012 Oct;13(14):2085-96.

[4]. Silodosin inhibits the growth of bladder cancer cells and enhances the cytotoxic activity of cisplatin via ELK1 inactivation.Am J Cancer Res. 2015 Sep 15;5(10):2959-68. eCollection 2015.

Pharmacodynamics
Sildoxine is an α1-adrenergic receptor antagonist. It exhibits the highest selectivity for the α1A-adrenergic receptor subtype, with an affinity 162 times higher than that of α1B-adrenergic receptors and approximately 50 times higher than that of α1D-adrenergic receptors. Clinical trials have shown that silodoxine improves maximum urinary flow rate, voiding symptoms, and storage symptoms in patients with benign prostatic hyperplasia. After oral administration, silodoxine has a rapid onset of action in male patients, relieving lower urinary tract symptoms within 2 to 6 hours. Sildoxine inhibits the human ether-a-go-go-related gene (HERG) tail current; however, its cardiovascular effects are relatively weak. Like all α1-adrenergic receptor antagonists that block α1-adrenergic receptors in the dilatational muscle of the iris, silodoxine may cause intraoperative iris relaxation syndrome (IFIS), characterized by miosis and iris bulging in patients taking α1-adrenergic receptor antagonists during cataract surgery.

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Silodoxine (KAD 3213; KMD 3213) is a highly selective α1A-adrenergic receptor antagonist used to treat benign prostatic hyperplasia (BPH)[1][3].
Its primary mechanism of action is to block α1A-adrenergic receptors in the smooth muscle of the prostate and the bladder neck, thereby leading to muscle relaxation, reduced bladder outlet obstruction, and improved lower urinary tract symptoms (LUTS)[1][3].
It is more than 1300 times more selective for α1A adrenergic receptors than for α1B adrenergic receptors. Compared with non-selective α1 receptor antagonists, this drug minimizes cardiovascular side effects (e.g., hypotension) [3]
Clinically indicated for the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) in adults [1][3]
In vitro studies have shown that this drug can inhibit bladder cancer cell proliferation and enhance the cytotoxicity of cisplatin by inactivating ELK1, suggesting its potential research value in combination therapy for bladder cancer [4]

C25H32F3N3O4

495.53

495.234

C, 60.60; H, 6.51; F, 11.50; N, 8.48; O, 12.91

160970-54-7

Silodosin-d4; 1426173-86-5

5312125

White to off-white solid powder

1.2±0.1 g/cm3

601.4±55.0 °C at 760 mmHg

107 °C

317.5±31.5 °C

0.0±1.8 mmHg at 25°C

1.552

2.52

3

9

13

35

654

1

FC(C([H])([H])OC1=C([H])C([H])=C([H])C([H])=C1OC([H])([H])C([H])([H])N([H])[C@]([H])(C([H])([H])[H])C([H])([H])C1C([H])=C(C(N([H])[H])=O)C2=C(C=1[H])C([H])([H])C([H])([H])N2C([H])([H])C([H])([H])C([H])([H])O[H])(F)F

PNCPYILNMDWPEY-QGZVFWFLSA-N

InChI=1S/C25H32F3N3O4/c1-17(30-8-12-34-21-5-2-3-6-22(21)35-16-25(26,27)28)13-18-14-19-7-10-31(9-4-11-32)23(19)20(15-18)24(29)33/h2-3,5-6,14-15,17,30,32H,4,7-13,16H2,1H3,(H2,29,33)/t17-/m1/s1

1-(3-hydroxypropyl)-5-[(2R)-2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]-2,3-dihydroindole-7-carboxamide

KAD 3213; KMD 3213; KMD 3213; KAD 3213; KMD-3213; KMD3213; KAD 3213; KAD3213; Silodosin; trade names: Rapaflo; Silodyx, Rapilif; Silodal; Urief; Urorec

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.05 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.05 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.05 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)