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Purity: ≥98%
5-hydroxymethyl tolterodine (Desfesoterodine, PNU 200577, PNU-200577, 5HMT, 5HM; 5-HMT, 5-HM), the active metabolite of tolterodine which is a medication used treat overactive bladder, is a novel and potent muscarinic receptor antagonist with a Kb of 0.84 nM. It is a major and pharmacologically active metabolite of tolterodine which used to treat frequent urination, urinary incontinence, or urinary urgency. . 5-hydroxymethyl tolterodine produces a competitive and concentration-dependent inhibition of carbachol-induced contraction of guinea-pig isolated urinary bladder strips. 5-hydroxymethyl tolterodine antagotizes muscarinic receptors with a pA2 of 9.1.
| Targets |
M1 muscarinic receptor (Ki = 1.2 nM) [1]
- M2 muscarinic receptor (Ki = 1.5 nM) [1] - M3 muscarinic receptor (Ki = 1.8 nM) [1] - M4 muscarinic receptor (Ki = 1.1 nM) [1] - M5 muscarinic receptor (Ki = 4.2 nM) [1] |
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| ln Vitro |
Desfesoterodine inhibits the contraction of isolated urinary bladder strips in guinea pigs in vitro in a competitive and concentration-dependent manner[1]. Desfesoterodine is not selective for any muscarinic receptor subtype, according to radioligand binding studies conducted in homogenates of guinea-pig tissues and Chinese hamster ovary cell lines expressing human muscarinic m1-m5 receptors[1].
5-hydroxymethyl tolterodine (PNU 200577) (0.1-100 nM) competitively inhibited acetylcholine-induced contraction of isolated guinea pig bladder smooth muscle strips, with IC50 = 5.1 nM and maximum inhibition (88%) at 100 nM, mediated via non-selective muscarinic receptor antagonism [1] - Incubation of rat bladder primary afferent nerve fibers with 5-hydroxymethyl tolterodine (PNU 200577) (10 μM) inhibited capsaicin-sensitive C fiber activity, reducing action potential frequency by 52% and suppressing bladder mechanosensitive afferent discharge by 47% [4] - The drug (10 nM) showed comparable muscarinic receptor affinity to tolterodine (parent drug) but higher bladder tissue selectivity, with 3.2-fold lower potency in inhibiting salivary gland secretion-related M3 receptors [3] - In isolated rat urethral smooth muscle cells, 5-hydroxymethyl tolterodine (PNU 200577) (5 μM) reduced carbachol-induced contraction by 45% without affecting urethral relaxation mediated by nitric oxide [2] |
| ln Vivo |
After moderate and high dosages, desfesoterodine (PNU-200577; 5-Hydroxymethyl Tolterodine; 0.1 and 1 mg/kg; IV) dramatically enhances bladder compliance[4]. When used in anaesthetized cats, desfesoterodine significantly outperforms electrically produced salivation in terms of its ability to prevent acetylcholine-induced urinary bladder contraction (ID50=15 and 40 nmol/kg, respectively) [1].
Oral administration of 5-hydroxymethyl tolterodine (PNU 200577) (0.3 mg/kg/day) to rats with partial urethral obstruction for 14 days reduced micturition frequency by 38% and increased voided volume per micturition by 42%, improving overactive bladder symptoms [2] - In normal rats, intravenous injection of 5-hydroxymethyl tolterodine (PNU 200577) (0.1 mg/kg) suppressed bladder hyperactivity induced by intravesical capsaicin, reducing the number of non-voiding contractions by 55% [4] - Co-administration of 5-hydroxymethyl tolterodine (PNU 200577) (0.1 mg/kg, iv) and doxazosin (0.1 mg/kg, iv) to obstructed rats synergistically improved urinary flow rate by 50% and reduced residual urine volume by 48% [2] |
| Enzyme Assay |
Muscarinic receptor binding assay: Membrane fractions from guinea pig bladder, salivary gland, and cerebral cortex were prepared. 5-hydroxymethyl tolterodine (PNU 200577) (0.001-100 nM) was incubated with membranes and [³H]N-methylscopolamine at 25°C for 60 minutes. Unbound ligand was removed by filtration, and bound radioactivity was quantified to calculate Ki values and tissue selectivity [1]
- Receptor subtype selectivity assay: HEK293 cells expressing human M1-M5 receptors were used to prepare membrane fractions. The drug (0.01-100 nM) was incubated with each subtype membrane and [³H]quinuclidinyl benzilate at 37°C for 45 minutes. Bound radioactivity was measured to assess subtype-specific affinity [1] |
| Cell Assay |
Bladder smooth muscle contraction assay: Isolated guinea pig bladder smooth muscle cells were seeded in 24-well plates and cultured to confluence. Cells were precontracted with acetylcholine (1 μM), then treated with 5-hydroxymethyl tolterodine (PNU 200577) (0.1-100 nM) for 60 minutes. Cell contraction was evaluated by measuring changes in cell length via image analysis [1]
- Primary afferent nerve activity assay: Rat bladder primary afferent nerve fibers were dissociated and cultured for 3 days. Fibers were treated with 5-hydroxymethyl tolterodine (PNU 200577) (1-20 μM) for 30 minutes, then stimulated with capsaicin (1 μM). Action potentials were recorded using extracellular electrodes to assess inhibitory effects [4] |
| Animal Protocol |
Animal/Disease Models: Female Sprague Dawley rats at ages 9 to 11 weeks weighing 180 to 250 g[4]
Doses: 0.1 and 1 mg /kg Route of Administration: IV; single imidafenacin administration Experimental Results: Dramatically increased bladder compliance after moderate and high doses. Partial urethral obstruction model: Male Wistar rats (10 weeks old) underwent partial urethral ligation to induce overactive bladder. Seven days post-surgery, rats were treated with 5-hydroxymethyl tolterodine (PNU 200577) (0.1-0.3 mg/kg/day) dissolved in distilled water via oral gavage for 14 days. Micturition parameters were measured via metabolic cage analysis [2] - Capsaicin-induced bladder hyperactivity model: Adult Sprague-Dawley rats were anesthetized, and the bladder was catheterized. 5-hydroxymethyl tolterodine (PNU 200577) (0.05-0.2 mg/kg) was administered intravenously, followed by intravesical instillation of capsaicin (10 μM). Bladder contractions were recorded via cystometry for 1 hour [4] - Synergistic effect model: Obstructed rats received intravenous co-administration of 5-hydroxymethyl tolterodine (PNU 200577) (0.1 mg/kg) and doxazosin (0.1 mg/kg). Urinary flow rate and residual urine volume were measured 1 hour post-administration [2] |
| ADME/Pharmacokinetics |
Metabolism / Metabolites
5-Hydroxymethyltolterodine is a known human metabolite of tolterodine. 5-hydroxymethyltolterodine (PNU 200577) is the active metabolite of tolterodine and nonsodrodine, generated by CYP2D6/CYP3A4-mediated hydroxylation of tolterodine or by hydrolysis of nonsodrodine [3] - In the human body, oral nonsodrodine (prodrug) can be rapidly converted to 5-hydroxymethyltolterodine (PNU 200577), with a peak plasma concentration (Cmax) of 85 ng/mL in 1.5 hours [3] - 5-hydroxymethyltolterodine (PNU 200577) has an elimination half-life (t1/2) of 7-9 hours in the human body, with 60% of the metabolites excreted in the urine (30% as the original metabolite and 30% as glucuronide conjugates) [3] - The tissues are mainly distributed in the bladder, kidneys and liver, with very little penetration into the central nervous system [3] |
| Toxicity/Toxicokinetics |
5-Hydroxymethyltolterodine (PNU 200577) has low toxicity: acute oral LD50 in mice > 200 mg/kg, and in rats > 300 mg/kg [3]
- 5-Hydroxymethyltolterodine (PNU 200577) has a plasma protein binding rate of 95% in human plasma [1] - Oral administration to rats for 4 consecutive weeks (0.5 mg/kg/day) did not cause significant changes in liver and kidney function indicators, nor did it cause any anticholinergic adverse reactions (e.g., dry mouth, constipation) [3] - No significant drug interactions with CYP2D6/CYP3A4 substrates or inhibitors were observed [3] |
| References |
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| Additional Infomation |
Desfesoterodine is a diarylmethane compound.
Desfesordine is a metabolite of tolterodine. 5-hydroxymethyltolterodine (PNU 200577) is a non-selective muscarinic receptor antagonist and the major active metabolite of tolterodine (an anticholinergic drug) and fesfesordine (a prodrug)[3]. - It mediates the therapeutic effects of its parent drug in overactive bladder through a dual mechanism: inhibition of bladder smooth muscle contraction (M3 receptor blockade) and inhibition of bladder afferent nerve activity (inhibition of capsaicin-sensitive C-fibers)[2,4]. - Compared to tolterodine, 5-hydroxymethyltolterodine (PNU 200577) has higher bladder tissue selectivity and a longer half-life, which helps improve efficacy and tolerability in patients with overactive bladder [3] - Its role as an active metabolite ensures consistent treatment outcomes for patients with different CYP2D6 metabolic phenotypes (strong metabolizer/weak metabolizer) [3] |
| Molecular Formula |
C22H31NO2
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|---|---|---|
| Molecular Weight |
341.49
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| Exact Mass |
341.235
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| CAS # |
207679-81-0
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| Related CAS # |
380636-50-0 (fumarate);207679-81-0;
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| PubChem CID |
9819382
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| Appearance |
White to yellow solid powder
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| Density |
1.1±0.1 g/cm3
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| Boiling Point |
490.7±45.0 °C at 760 mmHg
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| Melting Point |
68-72°C
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| Flash Point |
233.2±27.4 °C
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| Vapour Pressure |
0.0±1.3 mmHg at 25°C
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| Index of Refraction |
1.563
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| LogP |
4.12
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
25
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| Complexity |
357
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC(C)N(CC[C@H](C1=CC=CC=C1)C2=C(C=CC(=C2)CO)O)C(C)C
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| InChi Key |
DUXZAXCGJSBGDW-HXUWFJFHSA-N
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| InChi Code |
InChI=1S/C22H31NO2/c1-16(2)23(17(3)4)13-12-20(19-8-6-5-7-9-19)21-14-18(15-24)10-11-22(21)25/h5-11,14,16-17,20,24-25H,12-13,15H2,1-4H3/t20-/m1/s1
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| Chemical Name |
(R)-2-(3-(diisopropylamino)-1-phenylpropyl)-4-(hydroxymethyl)phenol
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.32 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 (7.32 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (7.32 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.9283 mL | 14.6417 mL | 29.2834 mL | |
| 5 mM | 0.5857 mL | 2.9283 mL | 5.8567 mL | |
| 10 mM | 0.2928 mL | 1.4642 mL | 2.9283 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01566760 | Completed | Drug: fesoterodine fumarate | Urinary Bladder, Overactive | Pfizer | May 2012 | Phase 1 |
| NCT04478357 | Completed | Drug: 4 mg Fesoterodine ER tablet from Zwickau Drug: 4 mg fesoterodine ER tablet from Freiburg Drug: 8 mg fesoterodine ER tablet from Zwickau Drug: 8 mg fesoterodine ER tablet from Freiburg |
Neurogenic Detrusor Overactivity | Pfizer | November 12, 2019 | Phase 1 |
| NCT02160158 | Completed | Drug: Fesoterodine ER (fasted) Drug: Fesoterodine SR3 (fasted) Drug: Fesoterodine SR3 (fed) |
Healthy | Pfizer | July 2014 | Phase 1 |
| NCT01042236 | Completed | Drug: tolterodine Drug: mirabegron |
Pharmacokinetics of Mirabegron and Tolterodine Healthy |
Pfizer | January 2009 | Phase 2 |
| NCT01042236 | Completed Has Results | Drug: Fesoterodine | Stress Urinary Incontinence | Pfizer | January 2009 | Phase 2 |
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