| Candidate ID: | R0944 |
| Source ID: | DB06207 |
| Source Type: | approved |
| Compound Type: |
small molecule
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| Compound Name: |
Silodosin
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| Synonyms: |
Silodosin
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| Molecular Formula: |
C25H32F3N3O4
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| SMILES: |
C[C@H](CC1=CC2=C(N(CCCO)CC2)C(=C1)C(N)=O)NCCOC1=CC=CC=C1OCC(F)(F)F
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| Structure: |
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| DrugBank Description: |
Silodosin is a selective antagonist of alpha(α)-1 adrenergic receptors that binds to the α<sub>1A</sub> subtype with the highest affinity. α1-adrenergic receptors regulate smooth muscle tone in the bladder neck, prostate, and prostatic urethra: the α<sub>1A</sub> subtype accounts for approximately 75% of α1-adrenoceptors in the prostate.
Silodosin was first approved by the FDA in October 2008 and it is also approved in Europe and Canada. Silodosin is available as oral capsules with common trade names Rapaflo and Urorec. It is indicated for the symptomatic treatment of benign prostatic hyperplasia in adults. Most commonly affecting males over the age of 40 years, benign prostatic hyperplasia is the non-malignant enlargement of the prostate gland, associated with lower urinary tract symptoms that have a negative impact on the quality of life of patients. Silodosin works by binding to α<sub>1A</sub>-adrenoceptors with high affinity and relaxing the lower urinary tract, thereby improving urinary symptoms and alleviating bladder outlet obstruction.
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| CAS Number: |
160970-54-7
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| Molecular Weight: |
495.5345
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| DrugBank Indication: |
Silodosin is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). It is not indicated for the treatment of hypertension.
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| DrugBank Pharmacology: |
Silodosin is an antagonist of α<sub>1</sub>-adrenoceptors. It has the highest selectivity for the α<sub>1A</sub>-adrenoceptor subtype, with a 162-fold greater affinity than α<sub>1B</sub>-adrenoceptor and about a 50-fold greater affinity than for α<sub>1D</sub>-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 α<sub>1</sub>-adrenoceptor antagonists blocking α<sub>1</sub>-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.
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| DrugBank MoA: |
The pathogenesis of benign prostatic hyperplasia is not fully understood: it is believed to involve several pathways, including inflammation, apoptosis, and cellular proliferation. Most drug therapies aim to alleviate symptoms of benign prostatic hyperplasia, silodosin included. Lower urinary tract symptoms of benign prostatic hyperplasia are categorized into three main groups: voiding or obstructive (hesitancy, slow stream, intermittency, incomplete emptying), storage or irritative (frequency, urgency, nocturia, urge urinary incontinence), and postmicturition (postvoid dribbling). Prostate contraction is the main contributor to lower urinary tract symptoms of benign prostatic hyperplasia. The smooth muscle tone of the prostate is regulated by α<sub>1A</sub>-adrenoceptors, which are the most highly expressed subtype of α<sub>1</sub>adrenoceptors in the human prostate tissue. It has been reported that blockade of α<sub>1A</sub>-adrenoceptors relieves bladder outlet obstruction. Blockade of α<sub>1D</sub>-adrenoceptors, another subtype found in prostate tissue, is believed to alleviate storage symptoms due to detrusor overactivity.
α<sub>1</sub>-adrenoceptors are G protein-coupled receptors: upon binding of its natural ligand, norepinephrine and epinephrine, leads to the activation of phospholipase C and downstream signalling molecules, including inositol triphosphate and diacylglycerol. Ultimately, there is an increase in intracellular calcium levels and, consequently, smooth muscle contraction. Silodosin is an antagonist of α<sub>1</sub>-adrenoceptors, with the highest selectivity for the α<sub>1A</sub>-adrenoceptor subtype. By blocking the α<sub>1A</sub>-adrenoceptor signalling pathway, silodosin promotes prostatic and urethral smooth muscle relaxation, thereby improving lower urinary tract symptoms such as voiding. Silodosin also targets afferent nerves in the bladder, relieving bladder overactivity and storage symptoms.
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| Targets: |
Alpha-1A adrenergic receptor antagonist; Alpha-1D adrenergic receptor antagonist; Alpha-1B adrenergic receptor antagonist; HERG human cardiac K+ channel blocker
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| Inclusion Criteria: |
Therapeutic strategy associated
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