Azosemide
(Synonyms: 阿佐塞米) 目录号 : GC38738Azosemide is a potent Na+–K+–2Cl? cotransporter NKCC1 inhibitor with IC50s of 0.246??M for hNKCC1A and 0.197??M for NKCC1B, respectively.
Cas No.:27589-33-9
Sample solution is provided at 25 µL, 10mM.
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Azosemide is a potent Na+–K+–2Cl? cotransporter NKCC1 inhibitor with IC50s of 0.246??M for hNKCC1A and 0.197??M for NKCC1B, respectively.
[1] Hampel P, et al. Sci Rep. 2018 Jun 29;8(1):9877.
Cas No. | 27589-33-9 | SDF | |
别名 | 阿佐塞米 | ||
Canonical SMILES | ClC1=CC(NCC2=CC=CS2)=C(C3=NN=NN3)C=C1S(N)(=O)=O | ||
分子式 | C12H11ClN6O2S2 | 分子量 | 370.84 |
溶解度 | DMSO: 250 mg/mL (674.15 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 2.6966 mL | 13.4829 mL | 26.9658 mL |
5 mM | 0.5393 mL | 2.6966 mL | 5.3932 mL |
10 mM | 0.2697 mL | 1.3483 mL | 2.6966 mL |
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Pharmacokinetics and pharmacodynamics of Azosemide
Biopharm Drug Dispos 2003 Oct;24(7):275-97.PMID:14520682DOI:10.1002/bdd.365.
Azosemide is used in the treatment of oedematous states and hypertension. The exact mechanism of action is not fully understood, but it mainly acts on both the medullary and cortical segments of the thick ascending limb of the loop of Henle. Delayed tolerance was demonstrated in humans by homeostatic mechanisms (principally an increase in aldosterone secretion and perhaps also an increase in the reabsorption of solute in the proximal tubule). After oral administration to healthy humans in the fasting state, the plasma concentration of Azosemide reached its peak at 3-4 h with an absorption lag time of approximately 1 h and a terminal half-life of 2-3 h. The estimated extent of absolute oral bioavailability in humans was approximately 20.4%. After oral administration of the same dose of Azosemide and furosemide, the diuretic effect was similar between the two drugs, but after intravenous administration, the effect of Azosemide was 5.5-8 times greater than that in furosemide. This could be due to the considerable first-pass effect of Azosemide. The protein binding to 4% human serum albumin was greater than 95% at Azosemide concentrations ranging from 10 to 100 microg/ml using an equilibrium dialysis technique. The poor affinity of human tissues to Azosemide was supported by the relatively small value of the apparent post-pseudodistribution volume of distribution (Vdbeta), 0.262 l/kg. Eleven metabolites (including degraded products) of Azosemide including M1, glucuronide conjugates of both M1 and Azosemide, thiophenemethanol, thiophencarboxylic acid and its glycine conjugate were obtained in rats. Only Azosemide and its glucuronide were detected in humans. In humans, total body clearance, renal clearance and terminal half-life of Azosemide were 112 ml/min, 41.6 ml/min and 2.03 h, respectively. Azosemide is actively secreted in the renal proximal tubule possibly via nonspecific organic acid secretory pathway in humans. Thus, the amount of Azosemide that reaches its site of action could be significantly modified by changes in the capacity of this transport system. This capacity, in turn, could be predictably changed in disease states, resulting in decreased delivery of the diuretic to the transport site, as well as in the presence of other organic acids such as nonsteroidal anti-inflammatory drugs which could compete for active transport of Azosemide. The urinary excretion rate of Azosemide could be correlated well to its diuretic effects since the receptors are located in the loop of Henle. The diuretic effects of Azosemide were dependent on the rate and composition of fluid replacement in rabbits; therefore, this factor should be considered in the evaluation of bioequivalence assessment.
Diuretics: a review and update
J Cardiovasc Pharmacol Ther 2014 Jan;19(1):5-13.PMID:24243991DOI:10.1177/1074248413497257.
Diuretics have been recommended as first-line treatment of hypertension and are also valuable in the management of hypervolemia and electrolyte disorders. This review summarizes the key features of the most commonly used diuretics. We then provide an update of clinical trials for diuretics during the past 5 years. Compared to other classes of medications, thiazide diuretics are at least as effective in reducing cardiovascular events (CVEs) in patients with hypertension and are more effective than β-blockers and angiotensin-converting enzyme inhibitors in reducing stroke. Observational cohort data and a network analysis have shown that CVEs are lowered by one-fifth from chlorthalidone when compared to the commonly used thiazide, hydrochlorothiazide. Relative to placebo, chlorthalidone increases life expectancy. In those aged 80 years and older, the diuretic, indapamide, lowers CVEs relative to placebo. The aldosterone antagonist, eplerenone, lowers total mortality in early congestive heart failure. The benefit of eplerenone following acute myocardial infarction (MI) is limited to administration within 3 to 6 days post-MI. Aldosterone antagonists have been shown to lower the incidence of sudden cardiac death and to reduce proteinuria. In the setting of heart failure, long acting loop diuretics Azosemide and torasemide are more effective in improving heart failure outcomes than the far more commonly used short acting furosemide. Evening dosing of diuretics appears to lower CVEs relative to morning dosing. In conclusion, diuretics are a diverse class of drugs that remain extremely important in the management of hypertension and hypervolemic states.
Azosemide kinetics and dynamics
Clin Pharmacol Ther 1983 Oct;34(4):454-8.PMID:6617067DOI:10.1038/clpt.1983.197.
Azosemide is a loop diuretic that may also affect sodium reabsorption at the proximal tubule. We gave intravenous and oral doses of the drug to normal subjects to examine its kinetic and dynamic parameters. In the fasting state a lag time of absorption of approximately 1 hr was followed by absorption t 1/2s and elimination t 1/2s of approximately 0.75 and 2 2.5 hr. Only 2% of an oral dose was excreted unchanged in the urine. After intravenous dosing the elimination t 1/2 was approximately 2 hr; 20% of a dose was recovered unchanged. Thus Azosemide has an estimated bioavailability of 10%. The relationship between urinary Azosemide excretion rate ("dose") and natriuretic response follows a sigmoid-shaped curve with a dose inducing half-maximal response of 9.3 +/- 2.6 micrograms/min, whereas it is 69.8, 12.1 and 1 microgram/min for furosemide, piretanide, and bumetanide respectively.
Azosemide, a "loop" diuretic, and furosemide
Clin Pharmacol Ther 1979 Apr;25(4):435-9.PMID:428188DOI:10.1002/cpt1979254435.
Azosemide is a new monosulfamyl diuretic which inhibits solute transport throughout the thick ascending limb of the loop of Henle. This study compared equal amounts of Azosemide and furosemide (20, 40, and 80 mg) in normal subjects. No differences occurred at any dose in volume, sodium, or chloride excretion when analyzed as cumulative excretion at 4, 8, or 12 hr. Azosemide 40 mg caused less potassium excretion than 40 mg of furosemide but there was no significant difference in the sodium/potassium excretion ratio. Analysis of the time course of effect showed that compared to furosemide Azosemide tended to have a slower onset of effect. Differences in site of action studies between Azosemide and furosemide did not manifest as differences in urinary or electrolyte excretion in our normal subjects.
CNS pharmacology of NKCC1 inhibitors
Neuropharmacology 2022 Mar 1;205:108910.PMID:34883135DOI:10.1016/j.neuropharm.2021.108910.
The Na-K-2Cl cotransporter NKCC1 and the neuron-specific K-Cl cotransporter KCC2 are considered attractive CNS drug targets because altered neuronal chloride regulation and consequent effects on GABAergic signaling have been implicated in numerous CNS disorders. While KCC2 modulators are not yet clinically available, the loop diuretic bumetanide has been used in clinical studies to treat brain disorders and as a tool for NKCC1 inhibition in preclinical models. Bumetanide is known to have anticonvulsant and neuroprotective effects under some pathophysiological conditions. However, as shown in several species from neonates to adults (mice, rats, dogs, and by extrapolation in humans), at the low clinical doses of bumetanide approved for diuresis, this drug has negligible access into the CNS, reaching levels that are much lower than what is needed to inhibit NKCC1 in cells within the brain parenchyma. Several drug discovery strategies have been used over the last ∼15 years to develop brain-permeant compounds that, ideally, should be selective for NKCC1 to eliminate the diuresis mediated by inhibition of renal NKCC2. The strategies employed to improve the pharmacokinetic and pharmacodynamic properties of NKCC1 blockers include evaluation of other clinically approved loop diuretics; development of lipophilic prodrugs of bumetanide; development of side-chain derivatives of bumetanide; and unbiased high-throughput screening approaches of drug discovery based on large chemical compound libraries. The main outcomes are that (1), non-acidic loop diuretics such as Azosemide and torasemide may have advantages as NKCC1 inhibitors vs. bumetanide; (2), bumetanide prodrugs achieve significantly higher brain levels of the parent drug and have lower diuretic activity; (3), the novel bumetanide side-chain derivatives do not exhibit any functionally relevant improvement of CNS accessibility or NKCC1 selectivity vs. bumetanide; (4) novel compounds discovered by high-throughput screening may resolve some of the inherent problems of bumetanide, but as yet this has not been achieved. Thus, further research is needed to optimize the design of brain-permeant NKCC1 inhibitors. Another major challenge is to identify the mechanisms whereby various NKCC1-expressing cellular targets of these drug within (e.g., neurons, oligodendrocytes or astrocytes) and outside the brain parenchyma (e.g., blood-brain barrier, choroid plexus, endocrine and immune system), as well as molecular off-target effects, might contribute to their reported therapeutic and adverse effects.