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Basmisanil, formerly known as RG1662, RO5186582, is a highly selective inverse agonist/negative allosteric modulator of α5 subunit-containing GABAA receptors which is under development by Roche for the treatment of cognitive impairment associated with Down syndrome. As of August 2015, it is in phase II clinical trials for this indication. Down syndrome (DS) is the most commonly identifiable genetic form of intellectual disability. Individuals with DS have considerable deficits in intellectual functioning (i.e., low intellectual quotient, delayed learning and/or impaired language development) and adaptive behavior.
Physicochemical Properties
| Molecular Formula | C21H20FN3O5S |
| Molecular Weight | 445.4654 |
| Exact Mass | 445.11 |
| CAS # | 1159600-41-5 |
| Related CAS # | 1159600-41-5 |
| PubChem CID | 57336276 |
| Appearance | White to off-white solid powder |
| Density | 1.4±0.1 g/cm3 |
| Boiling Point | 726.6±60.0 °C at 760 mmHg |
| Flash Point | 393.2±32.9 °C |
| Vapour Pressure | 0.0±2.4 mmHg at 25°C |
| Index of Refraction | 1.597 |
| LogP | 0.61 |
| Hydrogen Bond Donor Count | 0 |
| Hydrogen Bond Acceptor Count | 8 |
| Rotatable Bond Count | 5 |
| Heavy Atom Count | 31 |
| Complexity | 711 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | VCGRFBXVSFAGGA-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C21H20FN3O5S/c1-14-18(20(24-30-14)15-2-5-17(22)6-3-15)13-29-19-7-4-16(12-23-19)21(26)25-8-10-31(27,28)11-9-25/h2-7,12H,8-11,13H2,1H3 |
| Chemical Name | (1,1-dioxidothiomorpholino)(6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyridin-3-yl)methanone |
| Synonyms | RG 1662 RG-1662 RG1662 RO5186582 RO-5186582 RO 5186582 Basmisanil. |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| ln Vitro | Basmisanil (0.1 nM-100 μM) is more than 90 times more selective than α1 (Ki = 1031 nM), α2 (Ki = 458 nM), and α3 (Ki = 510 nM) subunit-containing receptors. It also exhibits strong affinity for the recombinant human GABAA-α5 receptor with a Ki value of 5 nM [1]. Basmisanil (1 nM-1 μM) exhibits an IC50 value of 8 nM, making it a highly selective inhibitor of GABAA-α5. At 1 μM, basmisanil suppresses GABA-induced currents on GABAA-α5, while having negligible or no impact on other receptor subtypes [1]. |
| ln Vivo | GABAA-α receptors in the rat brain are occupied by basmisanil (3-100 mg/kg, po) in a dose-dependent manner [1]. In rats and non-human primates, basmisanil (3–600 mg/kg po) enhances cognition without having anxiolytic or proconvulsant effects [1]. |
| Animal Protocol |
Animal/Disease Models: Sprague Dawley rat [1] (180 g; female) Doses: 3-100 mg/kg Route of Administration: Oral Experimental Results: Reduction in [3H]-Ro 15-4513 binding in a dose-dependent manner. At the highest dose (100 mg/kg), specific binding was diminished by 70% in the hippocampus. Animal/Disease Models: Lister Hooded rat, Wistar rat, and F-344 Fischer rat [1] (Lister Hooded rat: 220-250 g; male) (Wistar rat: 200-220 g; male and female) (F -344 Fischer Rat: 170-180 g; male) Doses: 3-600 mg/kg Route of Administration: Oral Experimental Results: Significant reduction of diazepam-induced deficits. Plasma concentrations were shown in a dose- and time-dependent manner, reaching a maximum level of 903 ng/mL (379 nM free plasma) 30 minutes after administration of 10 mg/kg. Animal/Disease Models: Male cynomolgus monkey [1] (cynomolgus monkey; 7-10 kg) Doses: 1-600 mg/kg Route of Administration: Oral Experimental Results: First reach correct on the 3rd difficult trial of the object retrieval task The percentage was Dramatically increased with the 10 mg/kg dose. An inverted U-shape |
| References |
[1]. Basmisanil, a highly selective GABA A-α5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man. Sci Rep. 2021 Apr 8;11(1):7700. |
| Additional Infomation |
Basmisanil has been used in trials studying the treatment and basic science of Down Syndrome. Drug Indication Treatment of down syndrome |
Solubility Data
| Solubility (In Vitro) | DMSO : ~100 mg/mL (~224.49 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.61 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 (5.61 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. Solubility in Formulation 3: ≥ 2.5 mg/mL (5.61 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2448 mL | 11.2241 mL | 22.4482 mL | |
| 5 mM | 0.4490 mL | 2.2448 mL | 4.4896 mL | |
| 10 mM | 0.2245 mL | 1.1224 mL | 2.2448 mL |