PF-06372865
目录号 : GC63145
PF-06372865 是一种具有口服活性的，α2/α3/α5 亚型选择性的 GABAA 正向变构调节剂 (PAM)。PF-06372865 是 α1/α2/α3/α5 亚基的高亲和力配体，对 α2，α1 PAM，α2 PAM 的 Ki 值分别为 2.9 nM，21 nM，134 nM，对 α4/α6 亚基的亲和力低。PF-06372865 可以透过血脑屏障 (BBB)。PF-06372865 具有抗焦虑活性，并且有用于癫痫研究的潜力。
Cas No.:1614245-70-3
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
PF-06372865 is an orally active, α2/α3/α5 subtype-selective GABAA positive allosteric modulator (PAM). PF-06372865 is a high affinity ligand at GABAA receptors containing α1/α2/α3/α5 subunits (Kis of 2.9 nM, 21 nM, 134 nM for α2, α1 PAM, α2 PAM, respectively), with low affinity for α4/α6 subunits. PF-06372865 can across the blood-brain barrier (BBB). PF-06372865 has anxiolytic activity and has the potential for epilepsy[1].
PF-06372865 (compound 34) has Ki values of 0.18 nM, 2.9 nM, 1.1 nM, 18 nM for human GABAA α1β3γ2, α2β2γ2, α3β3γ2, α5β2γ2 and 0.34 nM, 4.58 nM for rat GABAA α1β3γ2, α2β2γ2[1].
PF-06372865 (compound 34; 3, 10 mg/kg; orally; single dose) significantly increases the paw withdrawal threshold (PWT) in chronic constriction injury (CCI) animals[1]. PF-06372865 (0.3, 3, 10 mg/kg for mouse and 1, 3, 10 mg/kg for rat; orally) exhibits efficacy in two models of epilepsy, PTZ induced seizures (mouse), and amygdala kindling (rat)[1]. PF-06372865 (0.1, 0.32, 1, 3.2 and 10 mg/kg; orally) has anxiolytic activity at 3.2 and 10 mg/kg in elevated plus maze (male C57Bl/6 mice)[1]. PF-06372865 has a T1/2 of 1.1 hours, a Clp of 22 mL/min/kg, and a Vss of 2.1 L/kg for rats[1]. PF-06372865 has a T1/2 of 0.9 hours, a Clp of 29 mL/min/kg, and a Vss of 3.4 L/kg for dogs[1].
[1]. Owen RM, et al. Design and Identification of a Novel, Functionally Subtype Selective GABAA Positive Allosteric Modulator (PF-06372865). J Med Chem. 2019 Jun 27;62(12):5773-5796.
| Cas No. | 1614245-70-3 | SDF | |
| 分子式 | C22H21FN4O3S | 分子量 | 440.49 |
| 溶解度 | DMSO : 50 mg/mL (113.51 mM; Need ultrasonic) | 储存条件 | 4°C, protect from light |
| 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 | 2.2702 mL | 11.351 mL | 22.702 mL |
| 5 mM | 0.454 mL | 2.2702 mL | 4.5404 mL |
| 10 mM | 0.227 mL | 1.1351 mL | 2.2702 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 | ||||||||||
计算结果:
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。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
GABAkines - Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAA receptors
Pharmacol Ther 2022 Jun;234:108035.PMID:PMC9787737DOI:10.1016/j.pharmthera.2021.108035.
Positive allosteric modulators of γ-aminobutyric acid-A (GABAA) receptors or GABAkines have been widely used medicines for over 70 years for anxiety, epilepsy, sleep, and other disorders. Traditional GABAkines like diazepam have safety and tolerability concerns that include sedation, motor-impairment, respiratory depression, tolerance and dependence. Multiple GABAkines have entered clinical development but the issue of side-effects has not been fully solved. The compounds that are presently being developed and commercialized include several neuroactive steroids (an allopregnanolone formulation (brexanolone), an allopregnanolone prodrug (LYT-300), Sage-324, zuranolone, and ganaxolone), the α2/3-preferring GABAkine, KRM-II-81, and the α2/3/5-preferring GABAkine PF-06372865 (darigabat). The neuroactive steroids are in clinical development for post-partum depression, intractable epilepsy, tremor, status epilepticus, and genetic epilepsy disorders. Darigabat is in development for epilepsy and anxiety. The imidazodiazepine, KRM-II-81 is efficacious in animal models for the treatment of epilepsy and post-traumatic epilepsy, acute and chronic pain, as well as anxiety and depression. The efficacy of KRM-II-81 in models of pharmacoresistant epilepsy, preventing the development of seizure sensitization, and in brain tissue of intractable epileptic patients bodes well for improved therapeutics. Medicinal chemistry efforts are also ongoing to identify novel and improved GABAkines. The data document gaps in our understanding of the molecular pharmacology of GABAkines that drive differential pharmacological profiles, but emphasize advancements in the ability to successfully utilize GABAA receptor potentiation for therapeutic gain in neurology and psychiatry.
Analgesic potential of PF-06372865, an α2/α3/α5 subtype-selective GABAA partial agonist, in humans
Br J Anaesth 2019 Aug;123(2):e194-e203.PMID:30915991DOI:10.1016/j.bja.2018.12.006.
Background: This study investigated the analgesic effects of two doses (15 and 65 mg) of PF-06372865, a novel α2/α3/α5 gamma-aminobutyric acid A (GABAA) subunit selective partial positive allosteric modulator (PAM), compared with placebo and pregabalin (300 mg) as a positive control. Methods: We performed a randomised placebo-controlled crossover study (NCT02238717) in 20 healthy subjects, using a battery of pain tasks (electrical, pressure, heat, cold and inflammatory pain, including a paradigm of conditioned pain modulation). Pharmacodynamic measurements were performed at baseline and up to 10 h after dose. Results: A dose of 15 mg PF-06372865 increased pain tolerance thresholds (PTTs) for pressure pain at a ratio of 1.11 (90% confidence interval [CI]: 1.02, 1.22) compared with placebo. A dose of 65 mg PF-06372865 led to an increase in PTT for the cold pressor at a ratio of 1.17 (90% CI: 1.03, 1.32), and pressure pain task: 1.11 (90% CI: 1.01, 1.21). Pregabalin showed an increase in PTT for pressure pain at a ratio of 1.15 (95% CI: 1.06, 1.26) and cold pressor task: 1.31 (90% CI: 1.16, 1.48). Conclusion: We conclude that PF-06372865 has analgesic potential at doses that do not induce significant sedation or other intolerable adverse events limiting its clinical use. In addition, the present study established the potential role for this battery of pain tasks as a tool in the development of analgesics with a novel mechanism of action, for the treatment of various pain states including neuropathic pain and to establish proof-of-concept. Clinical trials registration: NCT0223871.
Safety, Tolerability, and Pharmacokinetics of Multiple Repeated Oral Doses of the α2/3/5-Subtype Selective GABAA -Positive Allosteric Modulator PF-06372865 in Healthy Volunteers
Clin Pharmacol Drug Dev 2021 Jul;10(7):756-764.PMID:33465277DOI:10.1002/cpdd.912.
Multiple-dose pharmacokinetics (PK) and safety were investigated in this phase 1 study of PF-06372865, a positive allosteric modulator of α2/3/5 subunit-containing γ-aminobutyric acid A receptors (NCT03351751). In 2 cohorts (7-8 PF-06372865 and 2 placebo in each cohort), healthy adult subjects received twice-daily oral doses of PF-06372865 for 21 days, which included titration in the first 7 days, followed by a maintenance dose of 25 mg twice daily (Cohort 1) and 42.5 mg twice daily (Cohort 2) for 14 days. Serial PK samples were collected on days 1 and 21. Nineteen subjects were assigned to study treatments; 18 completed the study. Approximate dose-proportional increases in maximum plasma concentratin and area under the plasma concentration-time curve over the dosing interval were observed. PF-06372865 was rapidly absorbed with a median time to maximum concentration of 1 to 2 hours following both single- and multiple-dose administration. Mean terminal elimination half-life on day 21 was approximately 11 hours in both cohorts. All adverse events were mild; the most frequently reported was dizziness. After titration, there were no reports of somnolence. There were no clinically significant safety findings, including a lack of withdrawal symptoms on discontinuation of treatment. These results demonstrate that PF-06372865 is safe and well tolerated at doses estimated to achieve high receptor occupancy (>80%), a profile differentiated from nonselective benzodiazepines.
Pronounced antiepileptic activity of the subtype-selective GABAA -positive allosteric modulator PF-06372865 in the GAERS absence epilepsy model
CNS Neurosci Ther 2019 Feb;25(2):255-260.PMID:30101518DOI:10.1111/cns.13046.
Aim: Antiepileptic drugs that modulate GABA have the potential to aggravate or improve the symptoms of absence epilepsy. PF-06372865 is a positive allosteric modulator (PAM) of α2/3/5 subunit-containing GABAA receptors with minimal activity at α1-containing receptors, which are believed to mediate many of the adverse events associated with benzodiazepines. The aim of this study was to assess the antiepileptic effect of PF-06372865 in a preclinical model of absence seizures. Methods: Genetic absence epilepsy rats from Strasbourg (GAERS) was implanted with four cortical electrodes over the frontoparietal cortex, and the number and cumulated duration of spike-and-wave discharges (SWDs) were recorded for 10-90 minutes following administration of vehicle, PF-06372865, and positive controls diazepam and valproate. Results: PF-06372865 (0.3, 1, 2, 10 mg kg-1 ) dose-dependently reduced the expression of SWDs, including full suppression at the highest doses by 30 minutes after administration. Conclusions: PF-06372865 demonstrated robust efficacy in suppressing SWDs in the GAERS model of absence epilepsy. To our knowledge, this is the first demonstration of antiepileptic activity of an α2/3/5-subtype-selective GABAA PAM in a model of absence epilepsy. Further study of the antiepileptic properties of PF-06372865 is warranted in patients with absence seizures.
A randomised, placebo-controlled clinical trial with the α2/3/5 subunit selective GABAA positive allosteric modulator PF-06372865 in patients with chronic low back pain
Pain 2018 Sep;159(9):1742-1751.PMID:29787472DOI:10.1097/j.pain.0000000000001267.
The effect of PF-06372865, a subtype-selective positive allosteric modulator of the γ-aminobutyric acid type A (GABAA) receptor, on chronic low back pain was investigated in a randomised, placebo- and active-controlled phase 2 clinical trial. The parallel treatment group trial consisted of a 1-week single-blind placebo run in the phase, followed by 4-week double-blind treatment. Patients were randomised to receive either PF-06372865, naproxen, or placebo twice a day for 4 weeks. The primary end point was the numerical rating score of low back pain intensity after 4 weeks of active treatment. Secondary end points included the Roland Morris Disability Questionnaire and the Hopkins Verbal Learning Test-Revised. The trial had predefined decision rules based on the probability that PF-06372865 was better than placebo. The study was stopped at the interim analysis for futility. At this time, a total of 222 patients were randomised and the mean PF-06372865 4-week response on the low back pain intensity was 0.16 units higher (worse) than placebo (90% confidence interval -0.28 to 0.60). There were small, statistically significant reductions in the delayed recall test score with PF-06372865, as measured by Hopkins Verbal Learning Test-Revised. The effects of naproxen were in line with expectations. PF-06372865 was well tolerated. The most common treatment-related adverse events in the PF-06372865 arm were somnolence (5 mild and 4 moderate), dizziness (2 mild and 3 moderate), and nausea (2 mild). Although the reason for the lack of analgesic effect is not completely clear, it may be a result of not achieving sufficient receptor occupancy to drive efficacy.