PDE4B Inhibitor
(Synonyms: KVA-D-88) 目录号 : GC47931A PDE4B inhibitor
Cas No.:2410550-31-9
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
PDE4B inhibitor is an inhibitor of phosphodiesterase 4B (PDE4B; IC50 = 140 nM).1,2 It is selective for PDE4B over a panel of 20 PDE isoforms and a panel of 39 CNS receptors at 10 µM but does inhibit the activity of PDE4C1, PDE3B, the serotonin (5-HT) receptor subtype 5-HT2C, and sigma-2 (σ2) receptors by greater than 50%.1 PDE4B inhibitor (1 µM) decreases LPS- or Pam3Cys-induced production of TNF-α in mouse bone marrow-derived macrophages (BMDMs). It reduces cocaine self-administration and the progressive ratio breakpoint in mice when administered at a dose of 5 mg/kg.2
1.Vadukoot, A.K., Sharma, S., Aretz, C.D., et al.Synthesis and SAR studies of 1H-pyrrolo[2,3-b]pyridine-2-carboxamides as phosphodiesterase 4B (PDE4B) inhibitorsACS Med. Chem. Lett.11(10)1848-1854(2020) 2.Burkovetskaya, M.E., Liu, Q., Vadukoot, A.K., et al.KVA-D-88, a novel preferable phosphodiesterase 4B inhibitor, decreases cocaine-mediated reward properties in vivoACS Chem. Neurosci.11(15)2231-2242(2020)
| Cas No. | 2410550-31-9 | SDF | |
| 别名 | KVA-D-88 | ||
| Canonical SMILES | O=C(N1CC(F)(C1)F)C2=CC3=C(N2C4=CC=C(C(Cl)=C4)Cl)N=CC=C3 | ||
| 分子式 | C17H11Cl2F2N3O | 分子量 | 382.2 |
| 溶解度 | DMF: 30 mg/ml,DMSO: 30 mg/ml,DMSO:PBS (pH 7.2) (1:5): 0.16 mg/ml | 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 | 2.6164 mL | 13.0822 mL | 26.1643 mL |
| 5 mM | 0.5233 mL | 2.6164 mL | 5.2329 mL |
| 10 mM | 0.2616 mL | 1.3082 mL | 2.6164 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。
BI 1015550 is a PDE4B Inhibitor and a Clinical Drug Candidate for the Oral Treatment of Idiopathic Pulmonary Fibrosis
Front Pharmacol 2022 Apr 20;13:838449.PMID:35517783DOI:10.3389/fphar.2022.838449.
The anti-inflammatory and immunomodulatory abilities of oral selective phosphodiesterase 4 (PDE4) inhibitors enabled the approval of roflumilast and apremilast for use in chronic obstructive pulmonary disease and psoriasis/psoriatic arthritis, respectively. However, the antifibrotic potential of PDE4 inhibitors has not yet been explored clinically. BI 1015550 is a novel PDE4 inhibitor showing a preferential enzymatic inhibition of PDE4B. In vitro, BI 1015550 inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor-α (TNF-α) and phytohemagglutinin-induced interleukin-2 synthesis in human peripheral blood mononuclear cells, as well as LPS-induced TNF-α synthesis in human and rat whole blood. In vivo, oral BI 1015550 shows potent anti-inflammatory activity in mice by inhibiting LPS-induced TNF-α synthesis ex vivo and in Suncus murinus by inhibiting neutrophil influx into bronchoalveolar lavage fluid stimulated by nebulized LPS. In Suncus murinus, PDE4 inhibitors induce emesis, a well-known gastrointestinal side effect limiting the use of PDE4 inhibitors in humans, and the therapeutic ratio of BI 1015550 appeared to be substantially improved compared with roflumilast. Oral BI 1015550 was also tested in two well-known mouse models of lung fibrosis (induced by either bleomycin or silica) under therapeutic conditions, and appeared to be effective by modulating various model-specific parameters. To better understand the antifibrotic potential of BI 1015550 in vivo, its direct effect on human fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) was investigated in vitro. BI 1015550 inhibited transforming growth factor-β-stimulated myofibroblast transformation and the mRNA expression of various extracellular matrix proteins, as well as basic fibroblast growth factor plus interleukin-1β-induced cell proliferation. Nintedanib overall was unremarkable in these assays, but interestingly, the inhibition of proliferation was synergistic when it was combined with BI 1015550, leading to a roughly 10-fold shift of the concentration-response curve to the left. In summary, the unique preferential inhibition of PDE4B by BI 1015550 and its anticipated improved tolerability in humans, plus its anti-inflammatory and antifibrotic potential, suggest BI 1015550 to be a promising oral clinical candidate for the treatment of IPF and other fibro-proliferative diseases.
Nanoparticle Delivery of Novel PDE4B Inhibitor for the Treatment of Alcoholic Liver Disease
Pharmaceutics 2022 Sep 7;14(9):1894.PMID:36145643DOI:10.3390/pharmaceutics14091894.
The incidence of alcoholic liver disease (ALD) is increasing worldwide while no effective treatment has been approved. The progression of ALD has proven to be related to the upregulation of phosphodiesterase 4 (PDE4) expression, and PDE4 inhibitors showed potential to improve ALD. However, the application of PDE4 inhibitors is limited by the gastrointestinal side effects due to PDE4D inhibition. Therefore, we used a novel PDE4B Inhibitor KVA-D88 as the therapeutic for ALD treatment. KVA-D88 inhibited inflammatory response, promoted β-oxidation, increased the level of antioxidants in the hepatocytes, and suppressed hepatic stellate cell (HSC) activation in vitro. To improve the solubility and availability in vivo, KVA-D88 was encapsulated into mPEG-b-P(CB-co-LA) nanoparticles (NPs) by solvent evaporation, with a mean particle size of 135 nm and drug loading of 4.2%. We fed the male C57BL/6 mice with a Lieber-DeCarli liquid diet containing 5% (v/v) ethanol for 6 weeks to induce ALD. Systemic administration of KVA-D88 free drug and KVA-D88-loaded NPs at 5 mg/kg significantly improved the ALD in mice. KVA-D88 significantly ameliorated alcohol-induced hepatic injury and inflammation. KVA-D88 also markedly reduced steatosis by promoting fatty acid β-oxidation. Liver fibrosis and reactive oxygen species (ROS)-caused cellular damage was observed to be alleviated by KVA-D88. KVA-D88-loaded NPs proved better efficacy than free drug in the animal study. In conclusion, the novel PDE4B Inhibitor KVA-D88-loaded NPs have the potential to treat ALD in mice.
A Novel Catecholopyrimidine Based Small Molecule PDE4B Inhibitor Suppresses Inflammatory Cytokines in Atopic Mice
Front Pharmacol 2018 May 11;9:485.PMID:29867490DOI:10.3389/fphar.2018.00485.
Degradation of cyclic adenosine mono phosphate (cAMP) by phosphodiesterase-4B (PDE-4B) in the inflammatory cells leads to elevated expression of inflammatory cytokines in inflammatory cells. Suppression of cytokines has proved to be beneficial in the treatment of atopic dermatitis (AD). Henceforth, application of PDE4B specific inhibitor to minimize the degradation of cAMP can yield better results in the treatment of AD. PDE4B specific inhibitor with a limited side effect is highly warranted. Herein, we synthesized a novel PDE4 inhibitor, compound 2 comprising catecholopyrimidine core functionalized with trifluoromethyl (-CF3) group. PDE4B inhibitory potential and specificity of novel compounds were evaluated by PDE inhibitor assay. In vivo efficacy of the compounds was analyzed using DNCB-induced NC/Nga mice. IgE, CD4+ T-helper cell infiltration, and cytokine profiles were analyzed by ELISA and immunohistochemistry techniques. Toluidine blue staining was performed for mast cell count. PDE4 inhibitor assay confirmed that compound 2 specifically inhibits PDE4B. In vivo analysis with DNCB-induced NC/Nga mice confirmed that compound 2 suppressed the levels of pro-inflammatory cytokines such as TNF-α, IL-4, IL-5, and IL-17. Furthermore, compound 2 significantly reduced the infiltrative CD4+ T-helper cells, mast cells and IgE levels in atopic tissue. The in vitro and in vivo data suggested that compound 2 specifically inhibit the PDE4B and the symptoms of the AD in atopic mice. Compound 2 might constitute a good candidate molecule for the treatment of AD.
PDE4B as a microglia target to reduce neuroinflammation
Glia 2016 Oct;64(10):1698-709.PMID:27038323DOI:10.1002/glia.22986.
The importance of microglia in immune homeostasis within the brain is undisputed. Their role in a diversity of neurological and psychiatric diseases as well as CNS injury is the subject of much investigation. Cyclic adenosine monophosphate (AMP) is a critical regulator of microglia homeostasis; as the predominant negative modulator of cyclic AMP signaling within microglia, phosphodiesterase 4 (PDE4) represents a promising target for modulating immune function. PDE4 expression is regulated by inflammation, and in turn, PDE4 inhibition can alter microglia reactivity. As the prototypic PDE4 inhibitor, rolipram, was tested clinically in the 1980s, drug discovery and clinical development of PDE4 inhibitors have been severely hampered by tolerability issues involving nausea and emesis. The two PDE4 inhibitors approved for peripheral inflammatory disorders (roflumilast and apremilast) lack brain penetration and are dose-limited by side effects making them unsuitable for modulating microglial function. Subtype selective inhibitors targeting PDE4B are of high interest given the critical role PDE4B plays in immune function versus the association of PDE4D with nausea and emesis. The challenges and requirements for successful development of a novel brain-penetrant PDE4B Inhibitor are discussed in the context of early clinical development strategies. Furthermore, the challenges of monitoring the state of microglia in vivo are highlighted, including a description of the currently available tools and their limitations. Continued drug discovery efforts to identify safe and well-tolerated, brain-penetrant PDE4 inhibitors are a reflection of the confidence in the rationale for modulation of this target to produce meaningful therapeutic benefit in a wide range of neurological conditions and injury. GLIA 2016;64:1698-1709.
New insights into PDE4B Inhibitor selectivity: CoMFA analyses and molecular docking studies
Mol Divers 2016 Feb;20(1):77-92.PMID:26290462DOI:10.1007/s11030-015-9631-1.
PDE4 inhibitors have been largely studied because of their promising therapeutic effects concerning inflammation and neurodegenerative dysfunctions, such as depression, schizophrenia and Alzheimer's diseases. In this context, the PDE4B isoform proved to be particularly involved in the activation of inflammatory responses, while the PDE4D subfamily is more associated with neuropathologies. The clinical use of PDE4 inhibitors was restricted by the presence of prominent side effects probably due to their non-specific action across the different isoforms. Therefore, this work deals with the development of 3D-QSAR models, supported by molecular docking studies, to identify the key requirements underlying selective PDE4B or PDE4D inhibition. The results highlighted the ligand-based approach as a promising tool to guide the rational design of novel PDE4 inhibitors endowed with high affinity and selectivity profiles. The alignment of compound 1-85 and the model A statistical results are depicted.