D159687
目录号 : GC34895
D159687是一种选择性PDE4D抑制剂。
Cas No.:1155877-97-6
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
D159687 is a selective PDE4D inhibitor[1]. PDE4D[1]
D159687 (1 μM, 0-24 hours) induces a transient increase in CREB phosphorylation which peaked at 6 hours after treatment[1].D159687 (0.01-1 μM, 6 hours) causes optimal CREB phosphorylation at 1 μM[1]. Western Blot Analysis[1] Cell Line: HT-22 (mouse hippocampal cell line)
D159687 (0.05-5 mg/kg; oral daily for a week) shows a potential recruitment or enhancement of synaptic function with increased task difficulty in female Cynomolgus macaques[2]. Animal Model: Female Cynomolgus macaques (4-6 year old) [2]
[1]. Zhang C, et al. Comparison of the Pharmacological Profiles of Selective PDE4B and PDE4D Inhibitors in the Central Nervous System. Sci Rep. 2017 Jan 5;7:40115.
| Cas No. | 1155877-97-6 | SDF | |
| Canonical SMILES | NC(NC1=CC=C(CC2=CC(C3=CC(Cl)=CC=C3)=C(OC)C=C2)C=C1)=O | ||
| 分子式 | C21H19ClN2O2 | 分子量 | 366.84 |
| 溶解度 | DMSO : 150 mg/mL (408.90 mM) | 储存条件 | Store at -20°C |
| 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 | 2.726 mL | 13.6299 mL | 27.2598 mL |
| 5 mM | 0.5452 mL | 2.726 mL | 5.452 mL |
| 10 mM | 0.2726 mL | 1.363 mL | 2.726 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 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 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % 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。
Compound D159687, a phosphodiesterase 4D inhibitor, induces weight and fat mass loss in aged mice without changing lean mass, physical and cognitive function
Biochem Biophys Res Commun 2018 Dec 2;506(4):1059-1064.PMID:30409425DOI:10.1016/j.bbrc.2018.10.180.
Aims: Therapies that recapitulate the health benefits of caloric restriction in older adults are needed. Phosphodiesterase 4 inhibitors demonstrate such promise. We examined their effects on body weight and composition, physical and cognitive function in aged mice using Compound D159687 (D159687). Methods: Nineteen 18-months old mice were randomized to receive either control (DMSO) or D159687 for seven weeks. We assessed food intake, body weight and body composition over time and performed once the following tests: treadmill, inverted grip strength, rotarod, spontaneous Y maze tests and skeletal muscle mitochondrial biogenesis. Results: Four of the D159687 treated mice died in the first week. Necropsy suggests acute lung injury. D159687 treated mice weighed more than control mice at baseline. After controlling for baseline weight, D159687 treated mice lost 4.2 grams(g) more weight than control mice, mainly from fat mass loss (p value < 0.001). Muscle mass was unchanged between the two mice groups. D159587 mice ate significantly more food than the control mice. We found no difference between the two groups in the results of treadmill, rotarod and spontaneous Y maze tests and in mitochondrial biogenesis. Conclusion: Compound D159687 induced weight loss, predominantly fat mass loss and increased food intake in aged mice. The caloric restriction and lean mass preservation potential of PDE4D inhibitors deserve further verification. Findings may have major therapeutic implications when translated to the older adult population. Although physical and cognitive parameters were unchanged in this study, further studies would be needed to verify these results. The high death rate in the D159687 treated mice may have been due to the technical aspects of oral gavage.
A negative allosteric modulator of PDE4D enhances learning after traumatic brain injury
Neurobiol Learn Mem 2018 Feb;148:38-49.PMID:29294383DOI:10.1016/j.nlm.2017.12.008.
Traumatic brain injury (TBI) significantly decreases cyclic AMP (cAMP) signaling which produces long-term synaptic plasticity deficits and chronic learning and memory impairments. Phosphodiesterase 4 (PDE4) is a major family of cAMP hydrolyzing enzymes in the brain and of the four PDE4 subtypes, PDE4D in particular has been found to be involved in memory formation. Although most PDE4 inhibitors target all PDE4 subtypes, PDE4D can be targeted with a selective, negative allosteric modulator, D159687. In this study, we hypothesized that treating animals with D159687 could reverse the cognitive deficits caused by TBI. To test this hypothesis, adult male Sprague Dawley rats received sham surgery or moderate parasagittal fluid-percussion brain injury. After 3 months of recovery, animals were treated with D159687 (0.3 mg/kg, intraperitoneally) at 30 min prior to cue and contextual fear conditioning, acquisition in the water maze or during a spatial working memory task. Treatment with D159687 had no significant effect on these behavioral tasks in non-injured, sham animals, but did reverse the learning and memory deficits in chronic TBI animals. Assessment of hippocampal slices at 3 months post-TBI revealed that D159687 reversed both the depression in basal synaptic transmission in area CA1 as well as the late-phase of long-term potentiation. These results demonstrate that a negative allosteric modulator of PDE4D may be a potential therapeutic to improve chronic cognitive dysfunction following TBI.
Selective PDE4B and PDE4D inhibitors produce distinct behavioral responses to ethanol and GABAergic drugs in mice
Neuropharmacology 2023 Jun 15;231:109508.PMID:36935006DOI:10.1016/j.neuropharm.2023.109508.
Apremilast is a phosphodiesterase (PDE) type 4 inhibitor that is nonselective at subtypes PDE4A-D. It modulates ethanol and GABAergic responses via protein kinase A (PKA) phosphorylation of specific GABAA receptor subunits and has opposite effects on ethanol-induced ataxia in wild-type and GABAA β3-S408/409A knock-in mice. We hypothesized that these different effects are due to preferential actions at different PDE4 subtypes. To test this hypothesis, we compared effects of selective PDE4 inhibitors on responses to ethanol and GABAergic drugs in male and female C57BL/6J mice. The PDE4B inhibitor A33 accelerated recovery from ataxia induced by ethanol and diazepam but did not alter ataxia induced by propofol. The PDE4D inhibitor D159687 accelerated recovery from diazepam-induced ataxia but prolonged recovery from ethanol- and propofol-induced ataxia. A33 shortened, while D159687 prolonged, the sedative-hypnotic effects of ethanol. Both drugs shortened diazepam's sedative-hypnotic effects. The modulatory effects of A33 and D159687 were completely prevented by the PKA inhibitor H89. Only D159687 prevented development of acute functional tolerance to ethanol-induced ataxia. D159687 transiently reduced two-bottle choice drinking in male and female mice that had consumed ethanol for 3 weeks and transiently reduced two-bottle choice, every-other-day drinking in male mice. A33 did not alter ethanol drinking in either procedure. Neither drug altered binge-like ethanol consumption or blood ethanol clearance. Thus, D159687 produced behavioral effects similar to apremilast, although it produced a more transient and smaller reduction in drinking. These results indicate that PDE4D inhibition contributes to apremilast's ability to reduce ethanol drinking, whereas PDE4B inhibition is not involved.
Comparison of the Pharmacological Profiles of Selective PDE4B and PDE4D Inhibitors in the Central Nervous System
Sci Rep 2017 Jan 5;7:40115.PMID:28054669DOI:10.1038/srep40115.
Inhibition of cyclic AMP (cAMP)-specific phosphodiesterase 4 (PDE4) has been proposed as a potential treatment for a series of neuropsychological conditions such as depression, anxiety and memory loss. However, the specific involvement of each of the PDE4 subtypes (PDE4A, 4B and 4C) in different categories of behavior has yet to be elucidated. In the present study, we compared the possible pharmacological effects of PDE4B and PDE4D selective inhibitors, A-33 and D159687, in mediating neurological function in mice. Both compounds were equally potent in stimulating cAMP signaling in the mouse hippocampal cell line HT-22 leading to an increase in CREB phosphorylation. In contrast, A-33 and D159687 displayed distinct neuropharmacological effects in mouse behavioral tests. A-33 has an antidepressant-like profile as indicated by reduced immobility time in the forced swim and tail suspension tasks, as well as reduced latency to feed in the novelty suppressed feeding test. D159687, on the other hand, had a procognitive profile as it improved memory in the novel object recognition test but had no antidepressant or anxiolytic benefit. The present data suggests that inhibitors targeting specific subtypes of PDE4 may exhibit differential pharmacological effects and aid a more efficient pharmacotherapy towards neuropsychological conditions.
Efficacy of selective PDE4D negative allosteric modulators in the object retrieval task in female cynomolgus monkeys (Macaca fascicularis)
PLoS One 2014 Jul 22;9(7):e102449.PMID:25050979DOI:10.1371/journal.pone.0102449.
Cyclic adenosine monophosphate (cAMP) signalling plays an important role in synaptic plasticity and information processing in the hippocampal and basal ganglia systems. The augmentation of cAMP signalling through the selective inhibition of phosphodiesterases represents a viable strategy to treat disorders associated with dysfunction of these circuits. The phosphodiesterase (PDE) type 4 inhibitor rolipram has shown significant pro-cognitive effects in neurological disease models, both in rodents and primates. However, competitive non-isoform selective PDE4 inhibitors have a low therapeutic index which has stalled their clinical development. Here, we demonstrate the pro-cognitive effects of selective negative allosteric modulators (NAMs) of PDE4D, D159687 and D159797 in female Cynomolgous macaques, in the object retrieval detour task. The efficacy displayed by these NAMs in a primate cognitive task which engages the corticostriatal circuitry, together with their suitable pharmacokinetic properties and safety profiles, suggests that clinical development of these allosteric modulators should be considered for the treatment of a variety of brain disorders associated with cognitive decline.