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Mirogabalin (DS-5565) is a potent, selective and orally bioavailable α2δ-1 ligand under development for treating pain associated with diabetic peripheral neuropathy, fibromyalgia, and postherpetic neuralgia. It has affinities for the α2δ subunit of voltage-gated calcium channels with Kds of 13.5 nM, 22.7 nM, 27 nM, and 47.6 nM for human α2δ-1, human α2δ-2, rat α2δ-1, and rat α2δ-2, respectively. Mirogabalin was estimated to be 17-fold more potent than pregabalin. Mirogabalin is being developed by Daiichi Sankyo and related to drugs such as gabapentin and pregabalin. Similarly to these drugs, mirogabalin binds to the α2δ calcium channels (1 and 2), but with significantly higher potency than pregabalin. It has shown promising results in Phase II clinical trials for the treatment of diabetic peripheral neuropathic pain.
| ln Vitro |
Mirogabalin (DS-5565) is a newly developed, highly potent, and selective α2δ-1 ligand for the α2δ-1 subunit of the voltage-sensitive calcium channel complex in the central nervous system (CNS). Milopalin dissociates from α2δ-1 more slowly than α2δ-2 and, in particular, α2δ-1 more slowly than pregabalin, according to in vitro investigations conducted with membrane preparations from human and rat α2δ subunit-expressing cells. In addition, compared to pregabalin, milopalin showed greater analgesic efficacy and broader central nervous system safety while demonstrating strong and prolonged analgesia in streptozotocin-induced diabetic rats. Its selectivity for α2δ-1 and slower dissociation as compared to pregabalin are the reasons for the range [1]. DS-5565, an α2δ-1 ligand, is being developed to treat postherpetic neuralgia, fibromyalgia, and diabetic peripheral neuropathy pain. Milopalin specifically targets α2δ-1, an auxiliary protein linked to voltage-sensitive calcium channel complexes in the brain. Numerous pain neurotransmitters are released less often as a result of this binding's reduction of calcium input into nerve terminals. Milopaline's estimated ED50 (converted scale) is 20.5 mg, with a 90% confidence interval (CI) ranging from 10.1-41.7 mg [2].
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| ln Vivo |
Furthermore, milopalin demonstrated strong and long-lasting analgesic effects in streptozotocin-induced diabetic rats. Its selectivity for α2δ-1 and slow dissociation are responsible for its superior analgesic efficacy and wider central nervous system (CNS) effects as compared to pregabalin safety margin. In contrast to pregabalin [1].
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| References |
[1]. Vinik A, et al. Efficacy and safety of Mirogabalin (DS-5565) for the treatment of diabetic peripheral neuropathic pain: a randomized, double-blind, placebo- and active comparator-controlled, adaptive proof-of-concept phase 2 study. Diabetes Care. 2014 Dec
[2]. Hutmacher MM, et al. Exposure-response modeling of average daily pain score, and dizziness and somnolence, forMirogabalin (DS-5565) in patients with diabetic peripheral neuropathic pain. J Clin Pharmacol. 2016 Jan;56(1):67-77. |
| Molecular Formula |
C12H19NO2
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|---|---|
| Molecular Weight |
209.2848
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| CAS # |
1138245-13-2
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| Related CAS # |
1138245-21-2 (besylate);1138245-13-2;
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| SMILES |
O=C(O)C[C@]1(CN)[C@]2([H])C=C(CC)C[C@]2([H])C1
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| InChi Key |
FTBQORVNHOIASH-CKYFFXLPSA-N
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| InChi Code |
InChI=1S/C12H19NO2/c1-2-8-3-9-5-12(7-13,6-11(14)15)10(9)4-8/h4,9-10H,2-3,5-7,13H2,1H3,(H,14,15)/t9-,10-,12-/m1/s1
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| Chemical Name |
2-((1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl)acetic acid
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| Synonyms |
DS-5565 DS 5565 DS5565 A-2000700 A2000700A 2000700Mirogabalin besylate Mirogabalin free base.
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| 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) |
H2O : ~7.71 mg/mL (~36.84 mM)
DMSO :< 1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.83 mg/mL (3.97 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 8.3 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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: ≥ 0.83 mg/mL (3.97 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 8.3 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: ≥ 0.83 mg/mL (3.97 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 10 mg/mL (47.78 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.7783 mL | 23.8914 mL | 47.7829 mL | |
| 5 mM | 0.9557 mL | 4.7783 mL | 9.5566 mL | |
| 10 mM | 0.4778 mL | 2.3891 mL | 4.7783 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.
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