Darifenacin
(Synonyms: 达非那新,(±)-UK-88525) 目录号 : GC35810
Darifenacin HBr (UK-88525) is a selective M3 muscarinic receptor antagonist with pKi of 8.9.
Cas No.:133099-04-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Darifenacin HBr (UK-88525) is a selective M3 muscarinic receptor antagonist with pKi of 8.9.
Darifenacin exerts non-parallel rightward displacement of the agonist curve and also significant depression of the maximum response (+)-cis-Dioxolane produced concentration-dependent contraction of the isolated bladder of rat. [1] Darifenacin produces a concentration dependent increase in R123 (P-gp probe) accumulation in MDCK cells. Darifenacin stimulates ATPase activity in P-gp membrane in a clear concentration dependent response manner with an estimated ED50 value of 1.6??M. Darifenacin (100 nM) shows a significantly greater permeability for darifenacin in the basolateral to apical direction resulting in an efflux ratio in BBMEC monolayers of approximately 2.6. [2]
Darifenacin produces dose-dependent inhibition of amplitude of volume-induced bladder contractions(VIBCAMP), producing 35% inhibition at dose of 283.3 nmol/kg and maximal inhibition of approximately 50–55%. [1] Darifenacin (0.1 mg/kg i.v.) reduces bladder afferent activity in both Aδ and C fibers in female Sprague-Dawley rats, the decrease in afferent spikes in C fibers may be more pronounced than that in Aδ fibers. [3] Darifenacin (7.5 mg and 15 mg, daily) reduces the number of incontinence episodes per week from baseline by 67.7% and 72.8% respectively compared with 55.9% with placebo in patients with overactive bladder (OAB). Darifenacin (7.5 mg and 15 mg, daily) also shows significantly superior to placebo for improvements in micturition frequency, bladder capacity, frequency of urgency, severity of urgency and number of incontinence episodes leading to a change in clothing or pads in patients with overactive bladder (OAB). [4]
[1] Hegde SS, et al. Br J Pharmacol, 1997, 120(8), 1409-1418. [2] Miller DW, et al. Neurourol Urodyn, 2011, 30(8), 1633-1638. [3] Iijima K, et al. Eur Urol, 2007, 52(3), 842-847.
| Cas No. | 133099-04-4 | SDF | |
| 别名 | 达非那新,(±)-UK-88525 | ||
| Canonical SMILES | O=C(N)C(C1=CC=CC=C1)([C@H]2CN(CCC3=CC=C(OCC4)C4=C3)CC2)C5=CC=CC=C5 | ||
| 分子式 | C28H30N2O2 | 分子量 | 426.55 |
| 溶解度 | DMSO : 100 mg/mL (234.44 mM; ultrasonic and warming and heat to 80°C) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.3444 mL | 11.722 mL | 23.4439 mL |
| 5 mM | 0.4689 mL | 2.3444 mL | 4.6888 mL |
| 10 mM | 0.2344 mL | 1.1722 mL | 2.3444 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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Darifenacin: in the treatment of overactive bladder
Drugs Aging 2004;21(13):885-92; discussion 893-4.PMID:15493952DOI:10.2165/00002512-200421130-00005.
Darifenacin is a selective muscarinic M3-receptor antagonist that has been evaluated in clinical trials in patients with overactive bladder syndrome (OAB) using a controlled-release formulation. In multicentre, randomised, double-blind trials in patients with OAB, Darifenacin 7.5 or 15 mg once daily for 12 weeks significantly reduced the frequency of urinary incontinence, frequency of micturition and frequency and severity of urgency versus placebo. A significant difference from placebo was apparent 2 weeks after starting treatment. At a dosage of 30 mg once daily, Darifenacin significantly prolonged warning time compared with placebo. Darifenacin 15 mg once daily for 2 weeks was as effective as oxybutynin 5 mg three times daily at reducing the frequency of urinary incontinence and frequency and severity of urgency in patients with OAB. Darifenacin was generally well tolerated in clinical trials. The most common adverse events were dry mouth and constipation. CNS tolerability appeared to be similar to that of placebo. Darifenacin had no adverse effect on cognitive function in healthy elderly volunteers.
Darifenacin: Pharmacology and clinical usage
Urol Clin North Am 2006 Nov;33(4):475-82, viii.PMID:17011383DOI:10.1016/j.ucl.2006.06.007.
Darifenacin is one of several recently approved antimuscarinics for the treatment of overactive bladder (OAB) and urge urinary incontinence. Darifenacin is an effective drug for the treatment of OAB and is tolerated by patients. Darifenacin's M3 selectivity is unique among antimuscarinics. This M3 selectivity could confer advantages in patients who have cardiovascular side effects (tachycardia), impaired cognition, complaints of dizziness, or sleep disturbances. In some studies, Darifenacin caused less dry mouth than oxybutynin. Rates of constipation, although significant, are tolerated and rarely a cause for discontinuation in clinical trials. This review describes the role of M3 receptors and covers the mechanism of action, pharmacokinetic properties, clinical efficacy safety and tolerability, drug interactions, and dosing guidelines for Darifenacin.
Darifenacin in the treatment of overactive bladder
Drugs Today (Barc) 2005 Jul;41(7):441-52.PMID:16193097DOI:10.1358/dot.2005.41.7.891719.
Darifenacin is a novel muscarinic M(3) selective receptor antagonist developed for the once-daily treatment of overactive bladder, a chronic, debilitating and highly prevalent condition affecting adults of all ages. Preclinical research has confirmed the pharmacological profile of Darifenacin as a potent antimuscarinic agent with up to 59-fold higher affinity for M(3) receptors than other muscarinic receptor subtypes and selectivity for the bladder over other tissues expressing these receptors. Extensive research in large, randomized, placebo-controlled trials have demonstrated that Darifenacin, at doses of 7.5 and 15 mg once daily (q.d.), is efficacious in the treatment of overactive bladder, improving the core symptoms of urinary urgency, urge incontinence, increased micturition frequency and bladder capacity. In addition, post-hoc analyses have shown that many patients can achieve clinically meaningful continence levels, e.g., > or =90% reduction in incontinence episodes or > or =7 consecutive dry days. These results are supported by significant improvements in quality of life, which have paralleled the overactive bladder symptom reductions. Both fixed and flexible Darifenacin dosing regimens produce these beneficial effects, which extend to the more vulnerable population of older patients. Hence, in conjunction with data showing that this agent has a good safety and tolerability profile, these findings indicate that Darifenacin may provide an effective alternative pharmacotherapy for the treatment of patients with overactive bladder.
Darifenacin hydro-bromide
Acta Crystallogr Sect E Struct Rep Online 2009 May 14;65(Pt 6):o1286.PMID:21583148DOI:10.1107/S1600536809017085.
In the title compound {systematic name: (S)-3-[(aminocar-bonyl)diphenylmethyl]-1-[2-(2,3-di-hy-dro-benzofuran-5-yl)ethyl]pyrrolidinium bromide}, C(28)H(31)N(2)O(2) (+)·Br(-), the pyrrolidine rings adopts an envelope conformation. The two phenyl rings make a dihedral angle of 72.5 (1)°. The four coplanar atoms of the pyrrolidine ring makes dihedral angles of 33.1 (2) and 82.8 (2)° with the two phenyl rings. The mol-ecular conformation is influenced by a C-H⋯O inter-action. In the crystal packing, there are two N-H⋯Br hydrogen bonds running in opposite directions. They appear to form C(10) and C(9) chain motifs in the unit cell. In addition, the mol-ecular packing is further stabilized by C-H⋯Br and C-H⋯O hydrogen bonds. The C atom bonded to the benzofuran ring system is disordered in a 0.66:0.34 ratio.
The clinical pharmacokinetics of Darifenacin
Clin Pharmacokinet 2006;45(4):325-50.PMID:16584282DOI:10.2165/00003088-200645040-00001.
Darifenacin hydrobromide is a selective muscarinic M(3) receptor antagonist that is indicated for use in treatment of overactive bladder disorder. Darifenacin was found to have a short terminal elimination half-life after intravenous and immediate-release oral dosage forms (3-4 hours) but this increased with a prolonged-release (PR) formulation (14-16 hours). The absolute bioavailability of Darifenacin from 7.5 and 15 mg PR tablets was estimated to be 15.4% and 18.6%, respectively. With repeated once-daily oral administration of the PR formulation, peak plasma concentrations of Darifenacin are achieved approximately 7 hours post-dose. After oral administration, Darifenacin is well absorbed from the gastrointestinal tract and very little unchanged drug (<2%) is recovered in the faeces. Steady state is achieved after 6 days of once-daily administration of the PR formulation. As expected, values of peak plasma concentration (C(max)) and area under the plasma concentration-time curve are dose dependent, although the increase in plasma concentrations is proportionally greater than the increase in dose owing to saturation of presystemic metabolism. From intravenous administration, it has been established that Darifenacin possesses a moderate-to-high hepatic extraction ratio, with high plasma clearance (36-52 L/h) and a volume of distribution (165-276L) that exceeds total body water. It is highly protein bound (98%), primarily to alpha(1)-acid glycoprotein. Darifenacin is subject to extensive hepatic metabolism, with 3% of unchanged drug excreted in urine and faeces. Metabolism is mediated by hepatic cytochrome P450 2D6 and 3A4, the main metabolic routes being monohydroxylation in the dihydrobenzfuran ring, dihydrobenzfuran ring opening, and N-dealkylation of the pyrrolidine nitrogen. Several possibly important drug-drug interactions have been identified with Darifenacin, including ketoconazole, erythromycin and fluconazole, each of which increases Darifenacin mean C(max) by 9.52-, 2.28- and 1.88-fold, respectively. When given with imipramine, Darifenacin causes 1.6-fold higher plasma concentrations of the antidepressant and its major metabolite. Moderate hepatic impairment, but not renal insufficiency, has been shown to increase plasma concentrations of the drug. The pharmacokinetic profile of Darifenacin is not affected by food.