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VX-745,p38 alpha MAPK抑制剂

强大的选择性p38 alpha MAPK抑制剂
规格或纯度: ≥98%
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mitogen-activated protein kinase 11 Inhibitor mitogen-activated protein kinase 14 Inhibitor
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基本描述

规格或纯度 ≥98%
英文名称 VX-745
别名 5-(2,6-Dichlorophenyl)-2-(2,4-difluorophenylthio)-6H-pyrimido[1,6-b]pyridazin-6-one
英文别名 5-(2,6-dichlorophenyl)-2-(2,4-difluorophenyl)sulfanylpyrimido[1,6-b]pyridazin-6-one；Neflamapimod
生化机理 VX-745 is highly potent and selective p38α inhibitor (IC50 = 10 nM). VX-745 also blocks TNFα production in LPS-stimulated HWB in vitro (IC50 = 177 nM). VX-745 displays 1000-fold selectivity over closely related kinases, including ERK1, MK2 and JNK1-3. VX-745 is a lead anti-inflammatory candidate, p38 MAPK inhibitor (IC50=10 nM) for the treatment of Rheumatoid arthritis (RA).Potent, selective p38 alpha\xa0MAPK inhibitor (IC 50 = 10 nM), with 20-fold selectivity over p38 beta\xa0and 1000-fold selectivity over closely related kinases, ERK1 and JNK1-3.VX-745 is a selective blood-brain barrier penetrant inhibitor of p38 MAPKα. VX-745 showed 20-fold selectivity for p38α over p38β and a Ki value of 220 nM. VX-745 has been shown to reduce inflammation in an arthritic (AIA) mouse model and to improve performance in aged rats.
储存温度 避光,-20°C储存
运输条件 超低温冰袋运输
备注 需要更多关于溶解度，用法和处理的建议吗？请访问我们的常见问题（FAQ）页面以获取更多详细信息。
产品介绍

产品介绍：

Neflamapimod (VX-745) 是有效的，可穿过血脑屏障的，高选择性的 p38α 抑制剂，对 p38α 的 IC50 值为 10 nM，p38β 的 IC50 值为 220 nM。Neflamapimod (VX-745) 具有抗炎活性。

名称和标识符

IUPAC Name 5-(2,6-dichlorophenyl)-2-(2,4-difluorophenyl)sulfanylpyrimido[1,6-b]pyridazin-6-one
INCHI InChI=1S/C19H9Cl2F2N3OS/c20-11-2-1-3-12(21)17(11)18-14-5-7-16(25-26(14)9-24-19(18)27)28-15-6-4-10(22)8-13(15)23/h1-9H
InChi Key VEPKQEUBKLEPRA-UHFFFAOYSA-N
Canonical SMILES C1=CC(=C(C(=C1)Cl)C2=C3C=CC(=NN3C=NC2=O)SC4=C(C=C(C=C4)F)F)Cl
分子式

C19H9Cl2F2N3OS
PubChem CID 3038525
分子量 436.27

化学和物理性质

溶解性 DMSO ≥60mg/mL Water <1.2mg/mL Ethanol <1.2mg/mL；Chloroform, DMSO, Methanol
敏感性 对光敏感
熔点 259-262°C (dec.)

靶标

Target ID 1499
名称 mitogen-activated protein kinase 14
缩写名 p38α
家族 p38 subfamily
别名 D7Ertd680e
基因和蛋白信息
Species Transmembrane Domains Amino Acids Chromosomal Location Gene Symbol Gene Name
Human 2 360 6p21.31 MAPK14 mitogen-activated protein kinase 14
Mouse 2 360 17 14.85 cM Mapk14 mitogen-activated protein kinase 14
Rat 2 360 20p12 Mapk14 mitogen activated protein kinase 14
Ensembl Gene ENSG00000112062 (Hs) , ENSMUSG00000053436 (Mm) , ENSRNOG00000000513 (Rn)
Entrez Gene 26416 (Mm) , 81649 (Rn) , 1432 (Hs)
OMIM 600289 (Hs)
Protein GI 20986516 (Hs) , 270341386 (Mm) , 62461582 (Rn)
UniProtKB P47811 (Mm) , P70618 (Rn) , Q16539 (Hs)
RefSeq Nucleotide NM_001168508 (Mm) , NM_001315 (Hs) , NM_031020 (Rn)
RefSeq Protein NP_001161980 (Mm) , NP_001161985 (Mm) , NP_001161986 (Mm) , NP_001306 (Hs) , NP_036081 (Mm) , NP_112282 (Rn)
ChEMBL Target CHEMBL2336 (Mm) , CHEMBL4825 (Rn) , CHEMBL260 (Hs)
Target ID 1500
名称 mitogen-activated protein kinase 11
缩写名 p38β
家族 p38 subfamily
别名 D7Ertd680e
基因和蛋白信息
Species Transmembrane Domains Amino Acids Chromosomal Location Gene Symbol Gene Name
Human 2 364 22q13.33 MAPK11 mitogen-activated protein kinase 11
Mouse 2 364 15 E3 Mapk11 mitogen-activated protein kinase 11
Rat 2 364 7q34 Mapk11 mitogen-activated protein kinase 11
Ensembl Gene ENSG00000185386 (Hs) , ENSMUSG00000053137 (Mm) , ENSRNOG00000006984 (Rn)
Entrez Gene 19094 (Mm) , 689314 (Rn) , 5600 (Hs)
OMIM 602898 (Hs)
Protein GI 20128774 (Hs) , 201023331 (Rn) , 168693637 (Mm)
UniProtKB Q15759 (Hs) , Q9WUI1 (Mm)
RefSeq Nucleotide NM_001109532 (Rn) , NM_002751 (Hs) , NM_011161 (Mm)
RefSeq Protein NP_001103002 (Rn) , NP_002742 (Hs) , NP_035291 (Mm)
DrugBank Target Q15759 (Hs)
ChEMBL Target CHEMBL4335 (Mm) , CHEMBL3961 (Hs)

关联配体

Ligand ID 5719
名称 neflamapimod
别名 VX 745
类别 Synthetic organic
学名 5-(2,6-dichlorophenyl)-2-(2,4-difluorophenyl)sulfanylpyridazino[6,1-f]pyrimidin-6-one
生物活性评价 Neflamapimod is brain-penetrant.
评价 Neflamapimod (VX-745) is an ATP-competitive inhibitor of mitogen-activated protein kinase p38α that was originally assessed in preclinical investigations for antiarthritic/antiinflammatory activity. More recently the compound is being repurposed since the p38α mechanism may modulate Alzheimer's specific inflammatory processes .
临床描述 This study will assess the effects of administration of VX-745 for 12 weeks on amyloid plaque burden in Alzheimer's disease (AD). Subjects who meet entry criteria will undergo 11C-PiB (Carbon-11-labeled Pittsburgh Compound B) positron emission tomography (PET) at baseline and after 45 days of dosing with VX-745. Cognitive testing will also be conducted at baseline and day 45.
This study will assess the effects of VX-745 on markers of disease in the central nervous system of patients with MCI due to AD or with mild AD. The study will also evaluate the safety and tolerability of VX-745 in these patients during 6 weeks of dosing, as well as the plasma and cerebrospinal fluid concentrations of VX-745 during dosing.
For this project, neflamapimod and placebo will be provided free of charge by the EIP company (www.eippharma.com). Neflamapimod is currently tested in 2 clinical trials in AD, one in Europe (The Netherlands) and one in the USA (clinical trials.gov/VX-745). The company commenced in May 2015 dosing in two phase 2a clinical studies in patients with Early AD: one in the Netherlands that is focused on PET amyloid imaging as the primary biomarker of drug effect, and one in the US (California) that is focused on Cerebrospinal fluid (CSF) evaluation to determine CSF drug concentrations and effects on inflammatory markers and disease biomarkers. Pharmacokinetic evaluation in these patients has demonstrated blood drug concentration levels in the predicted therapeutic range; and importantly, the data from the US study demonstrate that the drug achieves target drug concentrations in CSF, thus confirming the drug robustly enters the brain in humans. The present project offers us a unique chance to test this promising drug in AD patients. The aim of the study is to focus on PET neuroinflammation imaging as the primary biomarker of this drug effect. The chosen biomarker for imaging neuroinflammation in patients is [1 8F]-DPA714.
来源公司 EIP Pharma Inc
EIP Pharma Inc
University Hospital, Toulouse

参考文献

1. Fitzgerald CE, Patel SB, Becker JW, Cameron PM, Zaller D, Pikounis VB, O'Keefe SJ, Scapin G.  (2003)  Structural basis for p38alpha MAP kinase quinazolinone and pyridol-pyrimidine inhibitor specificity..  Nat Struct Biol,  10  (9):  (764-9).  [PMID:12897767]
2. Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT et al..  (2008)  A quantitative analysis of kinase inhibitor selectivity..  Nat Biotechnol,  26  (1):  (127-32).  [PMID:18183025]
3. Munoz L, Ralay Ranaivo H, Roy SM, Hu W, Craft JM, McNamara LK, Chico LW, Van Eldik LJ, Watterson DM.  (2007)  A novel p38 alpha MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer's disease mouse model..  J Neuroinflammation,  4  (13):  (21).  [PMID:17784957]
4. Duffy JP, Harrington EM, Salituro FG, Cochran JE, Green J, Gao H, Bemis GW, Evindar G, Galullo VP, Ford PJ et al..  (2011)  The Discovery of VX-745: A Novel and Selective p38α Kinase Inhibitor..  ACS Med Chem Lett,  2  (10):  (758-63).  [PMID:24900264]
5. Alam JJ.  (2015)  Selective Brain-Targeted Antagonism of p38 MAPKα Reduces Hippocampal IL-1β Levels and Improves Morris Water Maze Performance in Aged Rats..  J Alzheimers Dis,  48  (1):  (219-27).  [PMID:26401942]
6. Alam J, Blackburn K, Patrick D.  (2017)  Neflamapimod: Clinical Phase 2b-Ready Oral Small Molecule Inhibitor of p38α to Reverse Synaptic Dysfunction in Early Alzheimer's Disease..  J Prev Alzheimers Dis,  4  (4):  (273-278).  [PMID:29181493]

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