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Silodosin (KMD-3213; KMD3213; KAD3213; KAD-3213; Silodosin; trade names Rapaflo, Silodal, Silodyx, Rapilif, Urief, Urorec) is a highly selective alpha1A/α1A-adrenoceptor antagonist that was approved for the treatment of BPH-benign prostatic hyperplasia.
Physicochemical Properties
| Molecular Formula | C25H32F3N3O4 |
| Molecular Weight | 495.53 |
| Exact Mass | 495.234 |
| Elemental Analysis | C, 60.60; H, 6.51; F, 11.50; N, 8.48; O, 12.91 |
| CAS # | 160970-54-7 |
| Related CAS # | Silodosin-d4; 1426173-86-5 |
| PubChem CID | 5312125 |
| Appearance | White to off-white solid powder |
| Density | 1.2±0.1 g/cm3 |
| Boiling Point | 601.4±55.0 °C at 760 mmHg |
| Melting Point | 107 °C |
| Flash Point | 317.5±31.5 °C |
| Vapour Pressure | 0.0±1.8 mmHg at 25°C |
| Index of Refraction | 1.552 |
| LogP | 2.52 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 9 |
| Rotatable Bond Count | 13 |
| Heavy Atom Count | 35 |
| Complexity | 654 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | 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 |
| InChi Key | PNCPYILNMDWPEY-QGZVFWFLSA-N |
| InChi Code | 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 |
| Chemical Name | 1-(3-hydroxypropyl)-5-[(2R)-2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]-2,3-dihydroindole-7-carboxamide |
| Synonyms | KAD 3213; KMD 3213; KMD 3213; KAD 3213; KMD-3213; KMD3213; KAD 3213; KAD3213; Silodosin; trade names: Rapaflo; Silodyx, Rapilif; Silodal; Urief; Urorec |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | α1A-AR ( Ki = 0.036 nM ); α1B-AR ( Ki = 21 nM ); α1D-AR ( Ki = 2 nM ) | |
| ln Vitro |
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| ln Vivo |
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| Cell Assay |
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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| Animal Protocol |
Sprague Dawley rats 0.1-0.3mg/kg Intravenous injection |
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion The absolute bioavailability is approximately 32%. Following oral administration of silodosin 8 mg once daily in healthy male subjects, Cmax was 61.6 ± 27.54 ng/mL and AUC was 373.4 ± 164.94 ng x hr/mL. The Tmax was 2.6 ± 0.90 hours. Silodosin glucuronide or KMD-3213G, the main metabolite of silodosin, has an AUC three- or four fold higher than for the parent compound. A moderate fat or calorie meal reduces Cmax by 18% to 43% and AUC by 4% to 49%, as well as Tmax by about one hour. However, the US prescribing information recommends drug intake with meals to avoid the potential adverse effects associated with high plasma drug concentrations. At 10 days following oral administration of radiolabelled silodosin, about 33.5% of the dose was recovered in urine and 54.9% was recovered in feces. Silodosin has an apparent volume of distribution of 49.5 L. After intravenous administration, the plasma clearance of silodosin was approximately 10 L/hour. Metabolism / Metabolites The main metabolite of silodosin is silodosin glucuronide (KMD-3213G), which is a pharmacologically active metabolite formed by direct glucuronide conjugation mediated by UDP-glucuronosyltransferase 2B7 (UGT2B7). Silodosin glucuronide reaches plasma exposure (AUC) approximately four times greater than that of silodosin. The second major metabolite, KMD-3293, is formed from dehydrogenation catalyzed by alcohol and aldehyde dehydrogenases. KMD-3293 has negligible pharmacological activity and reaches plasma exposures similar to that of silodosin. Silodosin is also metabolized by CYP3A4, which catalyzes the oxidation reaction. Other than glucuronidation, dehydrogenation, and oxidation as its main metabolic pathways, silodosin can also undergo dealkylation (KMD-3289), N-dealkylation, hydroxylation, glucosylation, and sulfate conjugation. Metabolites of silodosin can undergo a series of further metabolic pathways. Biological Half-Life The elimination half-life of silodosin is 13.3 ± 8.07 hours. KMD-3213G, the main metabolite of silodosin, has an extended half-life of approximately 24 hours. |
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| Toxicity/Toxicokinetics |
Hepatotoxicity Silodosin has been associated with a low rate of serum aminotransferase elevations ( Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury). Protein Binding Silodosin is approximately 97% protein bound. |
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| References |
[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. |
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| Additional Infomation |
Pharmacodynamics Silodosin is an antagonist of α1-adrenoceptors. It has the highest selectivity for the α1A-adrenoceptor subtype, with a 162-fold greater affinity than α1B-adrenoceptor and about a 50-fold greater affinity than for α1D-adrenoceptor. In clinical trials, silodosin improved maximum urinary flow rate, voiding symptoms, and storage symptoms of benign prostatic hyperplasia. Following oral administration, silodosin had a rapid onset of effect in men, with early effects of relieving lower urinary tract symptoms occurring within two to six hours post-dose. Silodosin inhibited the human ether-a-go-go-related gene (HERG) tail current; however, it has weak cardiovascular effects. As with all α1-adrenoceptor antagonists blocking α1-adrenoceptors in the iris dilator muscle, silodosin may cause intraoperative floppy iris syndrome (IFIS), which is characterized by small pupils and iris billowing during cataract surgery in patients taking α1-AR antagonists. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
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. 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. 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0180 mL | 10.0902 mL | 20.1804 mL | |
| 5 mM | 0.4036 mL | 2.0180 mL | 4.0361 mL | |
| 10 mM | 0.2018 mL | 1.0090 mL | 2.0180 mL |