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| 5mg |
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| 10mg |
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| Targets |
PF-06372865 targets GABAA receptors with selectivity for α2/α3/α5 subunits. It is a high-affinity ligand for α1/α2/α3/α5 subunits with Ki values of 2.9 nM for α2, 21 nM for α1 PAM, and 134 nM for α2 PAM, and low affinity for α4/α6 subunits. As a positive allosteric modulator, it enhances GABA-mediated chloride influx without directly activating the receptor.
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| ln Vitro |
PF-06372865 (compound 34) has Ki values of 0.18 nM, 2.9 nM, 1.1 nM, and 18 nM against human GABAA α1β3η2, α2β2η2, α3β3η2, and α5β2η2; the values are 0.34 nM and 4.58 nM against rat GABAA α1β3η2 and α2β2η2 respectively[1].
In vitro, PF-06372865 demonstrates potent binding to GABAA receptor subunits with Ki values of 2.9 nM for α2, 21 nM for α1 PAM, and 134 nM for α2 PAM. It shows low affinity for α4/α6 subunits. As a positive allosteric modulator, it enhances GABA-induced currents in electrophysiological assays. The compound is brain-penetrant. |
| ln Vivo |
In rats suffering from chronic constrictive injury (CCI), PF-06372865 (Compound 34; 3, 10 mg/kg; oral; single dosage) dramatically raises the paw withdrawal threshold (PWT) [1]. PF-06372865 (mouse 0.3, 3, 10 mg/kg, rat 1, 3, 10 mg/kg; oral) exhibits effectiveness in two epilepsy models: amygdala kindling (rat) and PTZ-induced seizures (mouse) [1]. In the elevated plus maze (male C57Bl/6 mice), PF-06372865 (0.1, 0.32, 1, 3.2, and 10 mg/kg; oral) has anxiolytic action at 3.2 and 10 mg/kg [1]. Clp is 22 mL/min/kg, Vss is 2.1 L/kg, and the rat T1/2 for PF-06372865 is 1.1 hours[1]. The characteristics of PF-06372865 are as follows: T1/2 = 0.9 hours, Clp = 29 mL/min/kg, and Vss = 3.4 L/kg (dogs) [1].
In vivo, PF-06372865 has anxiolytic activity and is being investigated for epilepsy treatment. Its α2/α3/α5 subunit selectivity is expected to provide an improved safety and tolerability profile compared to non-selective GABAA modulators. The compound's brain penetration supports its central nervous system activity. |
| Enzyme Assay |
Specific cell-free enzyme/receptor binding assay protocols for PF-06372865 involve radioligand binding assays using membranes expressing recombinant GABAA receptor subunits. Ki values are determined for α1, α2, α3, α5, and α4/α6 subunits. Positive allosteric modulation is confirmed using electrophysiological recordings from cells expressing specific subunit combinations.
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| Cell Assay |
In vitro cell-based assays for PF-06372865 use cells expressing recombinant GABAA receptors with specific subunit combinations. Electrophysiological recordings (patch-clamp or two-electrode voltage-clamp) are performed to measure potentiation of GABA-evoked currents. Receptor binding assays using radiolabeled ligands confirm subunit selectivity and affinity.
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| Animal Protocol |
Animal/Disease Models: Chronic constriction injury (CCI) model (male Wistar rat) [1]
Doses: 3, 10 mg/kg Route of Administration: Oral Experimental Results: Paw withdrawal latency was Dramatically increased. In vivo animal studies for PF-06372865 have been conducted in models of anxiety and epilepsy. The compound's anxiolytic activity is assessed in rodent behavioral models. Its potential for epilepsy treatment is being investigated. The compound's brain penetration and target engagement are confirmed through pharmacokinetic and receptor occupancy studies. |
| ADME/Pharmacokinetics |
PF-06372865 (Darigabat) has a molecular formula of C22H21FN4O3S and a molecular weight of 440.49 g/mol. It has a LogP of 4.1215. The compound is soluble in DMSO at 50 mg/mL. Storage: 4°C, protect from light; in solvent: -80°C for 6 months or -20°C for 1 month (protect from light). It is orally active and brain-penetrant.
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| Toxicity/Toxicokinetics |
Specific toxicological data for PF-06372865 are not detailed in the available literature. The compound is classified for research use only and is not intended for human therapeutic applications. Its α2/α3/α5 subtype selectivity is designed to provide an improved safety and tolerability profile compared to non-selective GABAA modulators.
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| References | |
| Additional Infomation |
PF-06372865 (CAS 1614245-70-3), also known as Darigabat, is an orally active, α2/α3/α5 subtype-selective GABAA receptor positive allosteric modulator. It has Ki values of 2.9 nM for α2, 21 nM for α1 PAM, and 134 nM for α2 PAM. The compound is brain-penetrant and has anxiolytic activity. No clinical trial or approved indication data are available.
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| Molecular Formula |
C22H21FN4O3S
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| Molecular Weight |
440.490546941757
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| Exact Mass |
440.131
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| CAS # |
1614245-70-3
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| PubChem CID |
76287260
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| Appearance |
Off-white to yellow solid powder
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| LogP |
2.9
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
31
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| Complexity |
705
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S(CC)(C1C=CC(=C(C=1)OC)C1C(=CC=C(C=1)C1C=NN=C2C=1N=CN2CC)F)(=O)=O
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| InChi Key |
PTTQXDBPTFOCMT-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H21FN4O3S/c1-4-27-13-24-21-18(12-25-26-22(21)27)14-6-9-19(23)17(10-14)16-8-7-15(11-20(16)30-3)31(28,29)5-2/h6-13H,4-5H2,1-3H3
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| Chemical Name |
7-ethyl-4-[3-(4-ethylsulfonyl-2-methoxyphenyl)-4-fluorophenyl]imidazo[4,5-c]pyridazine
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| Synonyms |
PF-06372865 PF 06372865 PF06372865
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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 Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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) |
DMSO : ~50 mg/mL (~113.51 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.68 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 (5.68 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 (5.68 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 | 2.2702 mL | 11.3510 mL | 22.7020 mL | |
| 5 mM | 0.4540 mL | 2.2702 mL | 4.5404 mL | |
| 10 mM | 0.2270 mL | 1.1351 mL | 2.2702 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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