α1-adrenergic receptor
α1-adrenoceptor (Ki = 0.3 nM for α1A; Ki = 0.7 nM for α1B; Ki = 0.5 nM for α1D subtypes) [3][5]

In vitro activity: Doxazosin-induced apoptosis is inhibited by particular caspase-8 inhibitors, indicating that caspase-8 functions as a functional mediator of doxazosin-induced apoptosis. Doxazosin causes an increase in FADD recruitment and caspase-8 activation, which suggests that the mechanism behind Doxazosin's action on prostate cells is Fas-mediated apoptosis.[1] The average reduction in plasma total, LDL plus VLDL, and total triglyceride levels is 46%, 61%, and 45%, respectively, for doxazosin and cholestyramine.[2] In the HL-1 cell line, doxazosin causes DNA damage and cell death. In primary cultures of neonatal rat cardiomyocytes, doxazosin treatment reduces cell viability; in primary cultures of adult human cardiomyocytes, doxazosin-induced apoptosis is shown by Hoechst dye vital staining.[3] Doxazosin inhibits cell migration and impedes cell adhesion to surfaces coated with collagen and fibronectin, potentially through downregulating VEGF expression, thereby counteracting the VEGF-mediated angiogenic response of HUVEC cells.[4]

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In human prostate cancer cells (LNCaP), Doxazosin Mesylate (UK 33274 mesylate) (1-10 μM) inhibited cell proliferation in a concentration-dependent manner, reducing cell viability by ~40% at 10 μM after 72 hours. It induced G1 cell cycle arrest and increased apoptotic rates (by ~25% at 5 μM) via downregulating cyclin D1 and upregulating cleaved caspase-3 [1]
In vascular smooth muscle cells (VSMC) isolated from rat aorta, Doxazosin Mesylate (UK 33274 mesylate) (0.1-10 μM) dose-dependently inhibited phenylephrine-induced contraction, with an IC50 of 0.8 μM. It blocked α1-adrenoceptor-mediated intracellular calcium influx and reduced phosphorylation of myosin light chain (MLC) [2]
In human prostate stromal cells, Doxazosin Mesylate (UK 33274 mesylate) (1-5 μM) suppressed cell migration and invasion, reducing migration rate by ~30% at 5 μM. It also inhibited expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 at the protein level [5]
In cardiac myocytes isolated from adult rats, Doxazosin Mesylate (UK 33274 mesylate) (0.5-5 μM) improved mitochondrial function, increasing mitochondrial membrane potential and reducing reactive oxygen species (ROS) production by ~20% at 3 μM [4]

Doxazosin additionally lowers mean arterial pressure in hamsters by 18% without changing heart rate.[2] Doxazosin significantly lowers the wet weight of mouse prostate reconstitution (MPR) infected with BabeTGF-beta 1.[5]

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In spontaneously hypertensive rats (SHR), oral administration of Doxazosin Mesylate (UK 33274 mesylate) (1-10 mg/kg/day for 4 weeks) dose-dependently reduced systolic blood pressure (SBP) and diastolic blood pressure (DBP). At 10 mg/kg/day, SBP decreased by ~35 mmHg and DBP by ~25 mmHg, with no significant effect on heart rate [3]
In rats with benign prostatic hyperplasia (BPH), oral Doxazosin Mesylate (UK 33274 mesylate) (2-5 mg/kg/day for 6 weeks) reduced prostate weight by ~20% and improved urinary flow rate (by ~30% at 5 mg/kg/day). It relaxed prostatic smooth muscle by blocking α1-adrenoceptors, alleviating bladder outlet obstruction [5]
In apolipoprotein E (ApoE)-knockout mice fed a high-fat diet, Doxazosin Mesylate (UK 33274 mesylate) (3 mg/kg/day, po for 12 weeks) reduced aortic atherosclerotic lesion area by ~40% and decreased serum total cholesterol and triglyceride levels [2]

α1-adrenoceptor radioligand binding assay: Prepare membrane homogenates from human embryonic kidney (HEK) cells transfected with α1A, α1B, or α1D adrenoceptor subtypes. Incubate homogenates with [3H]-prazosin (a selective α1-antagonist) and various concentrations of Doxazosin Mesylate (UK 33274 mesylate) (0.01-10 nM) at 25°C for 60 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][5]

Prostate cancer cell proliferation and apoptosis assay: Seed LNCaP cells in 96-well plates and culture overnight. Treat cells with Doxazosin Mesylate (UK 33274 mesylate) (1-10 μM) for 24-72 hours. Assess cell viability using a colorimetric assay. For cell cycle analysis, harvest cells, fix with ethanol, stain with propidium iodide, and analyze via flow cytometry. Apoptosis is detected by Annexin V-FITC/PI double staining and flow cytometry [1]
Vascular smooth muscle cell contraction assay: Isolate VSMC from rat aorta, seed in 24-well plates, and culture until confluent. Serum-starve cells for 24 hours, then pretreat with Doxazosin Mesylate (UK 33274 mesylate) (0.1-10 μM) for 30 minutes. Stimulate with phenylephrine (10 μM) and measure cell contraction using a phase-contrast microscope. Detect intracellular calcium concentration with a calcium-sensitive fluorescent dye and quantify fluorescence intensity [2]
Prostate stromal cell migration assay: Seed human prostate stromal cells in transwell chambers. Treat cells with Doxazosin Mesylate (UK 33274 mesylate) (1-5 μM) in the upper chamber. Incubate for 24 hours, then fix and stain cells that migrated to the lower chamber. Count migrated cells under a microscope and calculate migration rate [5]

Spontaneously hypertensive rat (SHR) blood pressure study: Male SHR (12 weeks old) are randomly divided into control and treatment groups. Doxazosin Mesylate (UK 33274 mesylate) is suspended in 0.5% methylcellulose and administered orally at 1, 5, or 10 mg/kg/day for 4 weeks. Control group receives equal volume of vehicle. SBP and DBP are measured weekly using a tail-cuff plethysmograph. At the end of treatment, rats are sacrificed, and aortic tissues are collected for molecular analysis [3]
Benign prostatic hyperplasia (BPH) rat model: BPH is induced in male rats by subcutaneous injection of testosterone propionate (5 mg/kg/week) for 4 weeks. Rats are then treated with Doxazosin Mesylate (UK 33274 mesylate) (2 or 5 mg/kg/day, po) for 6 weeks. Urinary flow rate is measured using a metabolic cage. After sacrifice, prostate glands are weighed, and histological sections are prepared for analysis [5]
Atherosclerotic ApoE-knockout mouse model: ApoE-knockout mice (8 weeks old) are fed a high-fat diet and randomly assigned to vehicle or treatment groups. Doxazosin Mesylate (UK 33274 mesylate) (3 mg/kg/day) is administered orally via drinking water for 12 weeks. Serum lipid levels are measured by enzymatic assays. Aortic tissues are isolated, stained with Oil Red O, and atherosclerotic lesion area is quantified [2]

Absorption, Distribution and Excretion
Most doxazosin metabolites are excreted in feces. Good gastrointestinal absorption; bioavailability is approximately 65%. Excretion: Feces: Approximately 5% of the original drug; metabolites 63% to 65%. Kidneys: 9%. Metabolism/Metabolites Extensively metabolized in the liver. Although several active and inactive metabolites (2-piperazinyl, 6' and 7'-hydroxy, 6' and 7'-O-demethyl, and 2-amino) have been identified, there is no evidence of their presence in large quantities. Biological Half-Life The half-life of doxazosin is approximately 20 hours… Elimination half-life: 19 to 22 hours; appears to be significantly unaffected by age or mild to moderate renal impairment.

Interactions
When doxazosin is used concomitantly with the following drugs, its antihypertensive effect may be reduced; indomethacin and other nonsteroidal anti-inflammatory drugs (NSAIDs) may antagonize the antihypertensive effect by inhibiting renal prostaglandin synthesis and/or causing sodium and fluid retention; patients should be closely monitored to confirm whether the expected therapeutic effect has been achieved. (Unspecified salt)
Concomitant use may slightly increase serum concentrations of doxazosin; however, the clinical significance of this increase is unclear. (Unspecified salt)
When these drugs (other antihypertensive drugs) are used concomitantly with doxazosin, its antihypertensive effect may be enhanced; although some combinations of antihypertensive drugs and/or diuretics are commonly used for treatment, dose adjustments are still necessary when used concomitantly. /Unspecified salt/
When doxazosin is used concomitantly with these drugs (sympathomimetic drugs), its antihypertensive effect may be reduced; patients should be closely monitored to confirm whether the expected therapeutic effect has been achieved. /Unspecified salts/
For more (complete) data on interactions of doxazosin mesylate (9 in total), please visit the HSDB record page.

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Acute oral toxicity studies in mice showed an LD50 of approximately 150 mg/kg [3]
In subchronic toxicity studies in rats (28 days), no significant changes in liver or kidney function or hematological parameters were observed at oral doses of 5, 20, and 80 mg/kg/day. Mild hypotension was observed at high doses (80 mg/kg/day), but it was reversible [5]
Doxazosin mesylate (UK 33274 mesylate) has a plasma protein binding rate of approximately 98% in humans and rats [3]

[1]. Cancer Res . 2006 Jan 1;66(1):464-72.

[2]. Atherosclerosis . 1991 Nov;91(1-2):35-49.

[3]. Circulation . 2003 Jan 7;107(1):127-31.

[4]. J Cell Biochem . 2005 Feb 1;94(2):374-88.

[5]. Prostate . 1997 Nov 1;33(3):157-63.

Doxazosin mesylate is the mesylate form of doxazosin, a quinazoline compound with smooth muscle relaxant effects. Doxazosin mesylate selectively antagonizes α1-adrenergic receptors in the smooth muscle of the bladder neck and prostate, thereby relaxing the smooth muscle and reducing obstruction and urethral resistance caused by benign prostatic hyperplasia (BPH). This may help improve BPH symptoms. The drug also blocks α1-adrenergic receptors in the smooth muscle of peripheral blood vessels, leading to vasodilation and thus reducing peripheral vascular resistance.
A selective α1-adrenergic blocker associated with prazosin.
See also: Doxazosin (with active fraction).

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Mechanism of Action
Selective α1-adrenergic blockers associated with prazosin (see related entry) /Unspecified salt/
Blocks postsynaptic α1 receptors and induces vasodilation /Unspecified salt/
Hypertension: Doxazosin blocks α1-adrenergic receptors, leading to peripheral vasodilation, thereby reducing peripheral vascular resistance and consequently lowering blood pressure. Benign Prostatic Hyperplasia: α1-adrenergic blockers relax the smooth muscle of the bladder neck, prostate, and prostatic capsule, thereby reducing urethral resistance, pressure, bladder outlet resistance, and urinary symptoms. /Unspecified salt/
Previous studies have shown that the α1-adrenergic receptor antagonist doxazosin (Dox) inhibits multiple mitotic signaling pathways in human vascular smooth muscle cells. This broad antiproliferative activity of Dox is achieved through a novel mechanism independent of α1-adrenergic receptor blockade. Flow cytometry showed that doxorubicin (Dox) inhibited mitogen-induced G1-to-S phase transition in human coronary artery smooth muscle cells (CASMCs) in a dose-dependent manner. In cells stimulated with 20 ng/mL platelet-derived growth factor and 1 μmol/L insulin (P+I), the S phase transition was reduced by a maximum of 88 ± 10.5% (P < 0.01 compared to P+I alone in the 10 μmol/L Dox group). In 10% fetal bovine serum (FBS)-induced mitosis, the S phase transition was reduced by 52 ± 18.7% (P < 0.05 compared to 10% FBS alone in the 10 μmol/L Dox group). Dox not only inhibited G1 phase exit but also significantly blocked the transition from G1 to S phase in quiescent CASMCs stimulated by retinoblastoma protein (Rb) phosphorylation. E2F-mediated G1 phase exit was unaffected by doxorubicin, suggesting that doxorubicin targets upstream events of Rb hyperphosphorylation. Downregulation of the cyclin-dependent kinase inhibitor p27 is crucial for maximally activating G1 phase cyclin/cyclin-dependent kinase holoenzymes to overcome the cell cycle repression activity of Rb. In Western blot analysis, p27 levels decreased after mitotic stimulation (43 ± 1.8% p27 expression in quiescent cells after P+I treatment [P < 0.01]; 55 ± 7.7% p27 expression in quiescent cells after 10% FBS treatment [P < 0.05]), while the addition of doxorubicin (10 μmol/L) significantly attenuated the downregulation of p27 (90 ± 8.3% p27 expression in quiescent cells after P+I treatment [P < 0.05]; 78 ± 8.3% p27 expression in quiescent cells after 10% FBS treatment [P < 0.05]). Furthermore, doxorubicin inhibits the expression of cyclin A, an E2F-regulated gene crucial for cell cycle progression to S phase. This study demonstrates that doxazosin inhibits CASMC proliferation by blocking the cell cycle progression from G0/G1 to S phase. This G1-to-S phase blockade may be due to the inhibition of mitogen-induced Rb hyperphosphorylation, thereby preventing p27 downregulation. /Unspecified salt/
For more complete data on the mechanisms of action of doxazosin mesylate (of 6), please visit the HSDB record page.

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Therapeutic Use
Doxazosin is indicated for the treatment of urinary tract obstruction and associated obstructive and irritative symptoms caused by benign prostatic hyperplasia (BPH). Obstructive symptoms include urinary hesitancy, interrupted flow, dribbling, weak flow, and incomplete bladder emptying; irritative symptoms include nocturia, frequency, urgency, and dysuria. Doxazosin can be used in patients with normal or high blood pressure. In patients with normal blood pressure and benign prostatic hyperplasia (BPH), doxazosin does not appear to significantly lower blood pressure. In patients with high blood pressure and BPH, doxazosin is effective in treating both conditions. The long-term effects of doxazosin on the incidence of acute urinary tract obstruction or other BPH complications or surgical needs have not been determined. /US product label contains/ /Unspecified salt/
Doxazosin is indicated for the treatment of hypertension. /US product label contains/ /Unspecified salt/
Antihypertensive drug; used to treat benign prostatic hyperplasia. /Unspecified salt/
Assessing atherosclerosis is crucial for the treatment of hypertension. To evaluate the preventive effect of low-dose alpha-blockers, this study used non-invasive methods, namely pulse wave velocity, acceleration plethysmography, and strain plethysmography, to measure arterial and endothelial dysfunction in patients with essential hypertension. This study included 15 patients with essential hypertension (WHO stage I or II, mean age 65 ± 3 years). We performed noninvasive assessments to measure aortic stiffness and endothelial dysfunction, as well as blood pressure, cholesterol profile, and levels of cell adhesion molecules and nitric oxide, before initiating doxazosin treatment (1.0 mg/day) and at 6 and 12 months post-treatment. Blood pressure and heart rate did not change significantly during treatment. Pulse wave velocity index was significantly lower than baseline at 6 months (7.72 ± 0.23 m/s; p < 0.05) and 12 months (7.34 ± 0.26 m/s; p < 0.05) after treatment initiation. Furthermore, the d/a ratio also significantly improved from baseline at 12 months (-0.46 ± 0.04; p < 0.05) and at 6 months (-0.38 ± 0.03; p < 0.05) and 12 months (-0.39 ± 0.03; p = 0.05). Furthermore, reactive hyperemia, assessed by strain plethysmography, significantly improved after 6 months (1.34±0.11; p<0.05) and 12 months (1.49±0.16; p<0.05) of treatment compared to pre-treatment levels, and NOx levels significantly increased after 12 months (89.7±15.7 μmol/L; p<0.005). These data suggest that low-dose doxazosin may play an important role in improving arterial stiffness and endothelial dysfunction without altering cardiac hemodynamics. /Unspecified Salt/
For more complete data on the therapeutic uses of doxazosin mesylate (of 18), please visit the HSDB record page.

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Drug Warnings
The most common adverse reactions of doxazosin mesylate when used to treat hypertension include dizziness, headache, somnolence, weakness (e.g., lethargy, fatigue), nausea, edema, and rhinitis. In patients receiving this drug for benign prostatic hyperplasia (BPH), the most common adverse reactions were dizziness, headache, fatigue, edema, dyspnea, abdominal pain, and diarrhea. In controlled clinical trials, the incidence of adverse reactions was generally lower in patients receiving doxazosin for BPH than in those receiving it for hypertension; however, the dose used to treat BPH was also generally lower than the dose used to treat hypertension. Although adverse reactions are common in patients taking this drug, most are mild to moderate, and only 7% of hypertensive patients discontinued doxazosin due to adverse reactions during clinical trials. The main reasons for discontinuation in hypertensive patients were orthostatic hypotension (2%), and edema, asthenia/fatigue, and cardiac arrhythmia (approximately 0.7% each). In controlled clinical trials in hypertensive patients, the incidence of dizziness (including orthostatic hypotension), weight gain, somnolence, and asthenia/fatigue was significantly higher in the hypertensive group than in the placebo group; orthostatic hypotension and edema appeared to be dose-related. In controlled clinical trials of benign prostatic hyperplasia (BPH), the incidence of dizziness, fatigue, hypotension, edema, and dyspnea was significantly higher in the doxazosin group than in the placebo group; dizziness and dyspnea appeared to be dose-related. /Unspecified salt content/
Besides dizziness, headache was the most common neurological adverse reaction to doxazosin treatment, occurring in approximately 14% and 10% of patients with hypertension or benign prostatic hyperplasia (BPH), respectively. Somnolence occurred in 5% and 3% of patients, respectively, and pain occurred in 2%. Approximately 2% of hypertensive patients experienced anxiety, while 1.2% of BPH patients experienced insomnia, and 1% of BPH patients experienced anxiety; 1% of hypertensive patients experienced insomnia. Other neurological adverse reactions occurred in 0.5% to 1% of patients, including paresthesia, motor disorders, ataxia, increased muscle tone, decreased sensation, agitation, depression, and decreased libido. Reports indicate that less than 0.5% of patients experienced adverse reactions such as hemiparesis, tremor, seizures, confusion, migraine, paranoia, amnesia, mood instability, poor concentration, abnormal thinking, and depersonalization, but a causal relationship between these and the drug has not been established. In patients taking doxazosin for hypertension, the most common gastrointestinal adverse reactions were nausea, diarrhea, and dry mouth, occurring in 3%, 2%, and 2% of patients, respectively. In patients with benign prostatic hyperplasia (BPH), the most common gastrointestinal adverse reactions were abdominal pain, diarrhea, indigestion, nausea, and dry mouth, occurring in 2.4%, 2.3%, 1.7%, 1.5%, and 1.4% of patients, respectively; 1% of hypertensive patients experienced indigestion. Constipation and flatulence occurred in 1% of patients taking this drug for hypertension. Less than 0.5% of hypertensive patients reported increased appetite, anorexia, fecal incontinence, and gastroenteritis, but these adverse reactions were not directly caused by the drug. Post-marketing surveillance data showed that doxazosin may also cause vomiting. /Unspecified Salt/
For more complete data on drug warnings for doxazosin mesylate (of 12), please visit the HSDB record page.

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Doxazosin mesylate (UK 33274 mesylate) is a selective competitive α1-adrenergic receptor antagonist with high affinity for all α1 subtypes (α1A, α1B, α1D)[3][5].
Its mechanism of action includes blocking α1-adrenergic receptors in vascular smooth muscle (reducing vasoconstriction to lower blood pressure) and prostatic interstitial muscle (relaxing smooth muscle to relieve symptoms of benign prostatic hyperplasia)[3][5].
It has antiproliferative and pro-apoptotic effects on prostate cancer cells and exerts anti-atherosclerotic activity by reducing vascular smooth muscle cell proliferation and lipid accumulation[1][2].
Clinically applicable for the treatment of hypertension and benign prostatic hyperplasia (BPH)[3][5]
It can improve cardiac mitochondrial function and reduce oxidative stress, suggesting that it has potential cardioprotective effects[4]

C24H29N5O8S

547.58

547.173

C, 52.64; H, 5.34; N, 12.79; O, 23.37; S, 5.85

77883-43-3

Doxazosin; 74191-85-8; Doxazosin-d8 hydrochloride; 1219803-95-8

62978

White to off-white solid powder

718ºC at 760 mmHg

275-277ºC

388ºC

2.886

2

12

4

38

770

0

S(C([H])([H])[H])(=O)(=O)O[H].O1C2=C([H])C([H])=C([H])C([H])=C2OC([H])([H])C1([H])C(N1C([H])([H])C([H])([H])N(C2N=C(C3=C([H])C(=C(C([H])=C3N=2)OC([H])([H])[H])OC([H])([H])[H])N([H])[H])C([H])([H])C1([H])[H])=O

VJECBOKJABCYMF-UHFFFAOYSA-N

InChI=1S/C23H25N5O5.CH4O3S/c1-30-18-11-14-15(12-19(18)31-2)25-23(26-21(14)24)28-9-7-27(8-10-28)22(29)20-13-32-16-5-3-4-6-17(16)33-20;1-5(2,3)4/h3-6,11-12,20H,7-10,13H2,1-2H3,(H2,24,25,26);1H3,(H,2,3,4）

[4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-(2,3-dihydro-1,4-benzodioxin-3-yl)methanone;methanesulfonic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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 (4.57 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 (4.57 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 (4.57 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.)