BIRB 796 (Doramapimod) 化学構造
分子量: 527.66

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Quality Control & MSDS

製品説明

  • Compare p38 MAPK Inhibitors
    p38 MAPK製品生物活性の比較
  • 研究分野
  • BIRB 796 (Doramapimod)のメカニズム

製品の説明

生物活性

製品説明 BIRB 796 (Doramapimod)はp38αMAPKの高さ選択阻害剤、THP-1細胞に作用する時、EC50が18nMになる。
ターゲット

p38α MAPK

IC50

0.1 nM (Kd) [1]

In vitro試験 BIRB 796 shows no significant inhibition to ERK-1, SYK, IKK2β, ZAP-70, EGF receptor kinase, HER2, protein kinase A (PKA), PKC, PKC-α, PKC-β (I and II) and PKC-γ. BIRB 796 greatly improves binding affinity by forming a hydrogen bond between the morpholine oxygen and the ATP-binding domain of p38α. BIRB 796 represents one of the most potent and slowest dissociating inhibitors against human p38 MAP kinase now known. [1] BIRB 796 potently inhibits c-Raf-1 and Jnk2α2 with IC50 of 1.4 and 0.1 nM, respectively. [2] BIRB796 also inhibits the activity and the activation of SAPK3/p38γ at a higher concentration than it does in p38α. BIRB796 blocks the stress-induced phosphorylation of the scaffold protein SAP97, which is a physiological substrate of SAPK3/p38γ. BIRB796 blocks JNK1/2 activation and activity in HEK293 cells, while not inhibits the activation and activity of ERK1/ERK2 in Hela cells. Moreover, the binding of BIRB796 to the p38 MAPKs or JNK1/2 is impairing their phosphorylation by the upstream kinase MKK6 or MKK4 rather than enhancing their dephosphorylation. [3] BIRB 796 blocks baseline and bortezomib-triggered upregulation of p38 MAPK and Hsp27 phosphorylation, thereby enhancing cytotoxicity and caspase activation. BIRB 796 downregulates IL-6 and VEGF secretion in BMSCs triggered by TNF-α and TGF-β1. [4] BIRB-796 has a pyrazole scaffold that places a lipophilic t-butyl group into the lower selectivity site and a tolyl ring into the upper selectivity site. BIRB-796 also inhibits B-Raf and Abl with IC50 of 83 nM and 14.6 μM, respectively. [5]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
EoL-1-cell NGLsZ4tIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NU\FVlBkUUN3ME2wMlM1PzZ|IN88US=> M1nNNnNCVkeURWK=
DU-145 MWjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MkTnTWM2OD1|LkmzPFEyKM7:TR?= NInFTlZUSU6JUlXS
GOTO MYTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NELp[HdKSzVyPU[uN|kyPjFizszN NFHUT4lUSU6JUlXS
NCI-H358 NYC2VXpmT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M3TMOGlEPTB;Nz61N|gh|ryP NGjOb|JUSU6JUlXS
IST-MES1 M{XyUmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NYi1fnV[UUN3ME23Mlk2PjN5IN88US=> M{DweXNCVkeURWK=
KP-N-YN M1vvdmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M4\1TmlEPTB;OD6yNFE6KM7:TR?= M4ntc3NCVkeURWK=
T-24 M{LQNmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 Mn72TWM2OD16LkSwOlc{KM7:TR?= Ml;oV2FPT1KHUh?=
MPP-89 MYTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MUDJR|UxRThwNE[yOVEh|ryP NFHL[4dUSU6JUlXS
NCI-SNU-1 MojJS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NWnBSYl7UUN3ME25MlA3PzN7IN88US=> NUjBOJMzW0GQR2LFVi=>
BFTC-905 Ml\5S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NYDtU5Y3UUN3ME2xNE4yOjN|IN88US=> MUnTRW5IWkWU
MS-1 NEToOZdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NIW5foxKSzVyPUGwMlgzOzVizszN MV\TRW5IWkWU
NBsusSR NWnlVHRvT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MXLJR|UxRTFyLkiyN|Uh|ryP M1vOSXNCVkeURWK=
BEN MkGzS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MX7JR|UxRTF|LkGyOlQh|ryP NV;zS3B2W0GQR2LFVi=>
HMV-II MnvnS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NWDuVHRRUUN3ME2xOE4zOzB7IN88US=> MVLTRW5IWkWU
NCI-H1581 M{SzR2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MmjhTWM2OD1zNz6wOFQ4KM7:TR?= NGe5clhUSU6JUlXS
ES8 M1TO[2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NG\UO45KSzVyPUG3MlE3PyEQvF2= MkjUV2FPT1KHUh?=
LC-2-ad MmXvS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NHXBWmVKSzVyPUG3MlQ{PjZizszN MnjCV2FPT1KHUh?=
EW-13 NH\LfnJIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NFz4SINKSzVyPUG3Mlk2OTZizszN NVqxe2pKW0GQR2LFVi=>
AN3-CA NIHINHJIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NXjVc2hrUUN3ME2xPE4yKM7:TR?= M{jGTnNCVkeURWK=
DB NV3uU48{T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M2j5bGlEPTB;MUiuO|kzOyEQvF2= NFXrbVZUSU6JUlXS
SK-MEL-1 MnvBS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NU\oWld[UUN3ME2yNE4{Pjh|IN88US=> MV3TRW5IWkWU
CAPAN-1 NGrsRXhIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M3iy[mlEPTB;MkKuNVg5PCEQvF2= M2DLUnNCVkeURWK=
NCI-H2228 MoXzS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M4Pn[mlEPTB;MkOuOlY3QCEQvF2= NFnYNo1USU6JUlXS
HOP-92 MUXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NHzR[WxKSzVyPUK0MlM5OzhizszN Ml6yV2FPT1KHUh?=
KYSE-270 NFLJXlZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M1zlPWlEPTB;MkSuOVU4OyEQvF2= MXzTRW5IWkWU
HCC1806 NIrjbVRIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MVXJR|UxRTJ2Lke3PVkh|ryP NGjhZ2xUSU6JUlXS
HuO-3N1 M4O3NGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MlLvTWM2OD1{NT64NVg2KM7:TR?= NELwWoxUSU6JUlXS
HOS M1LnR2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MYjJR|UxRTJ3LkmyPVIh|ryP MnvMV2FPT1KHUh?=
KYSE-510 NX3FTZRXT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1rVRmlEPTB;Mk[uNVYyOiEQvF2= NIrje3lUSU6JUlXS
COLO-741 MWPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MkHTTWM2OD1{Nj6zN|I6KM7:TR?= MX;TRW5IWkWU
H-EMC-SS M1i3NWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NHrEW4tKSzVyPUK2MlkzPDVizszN NEn3fZdUSU6JUlXS
HCC1937 NXvvXmNoT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NFzs[mtKSzVyPUK3MlIzOzhizszN NIWyeYVUSU6JUlXS
NCI-H2126 NGf6UHVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MonBTWM2OD1{Nz6zPVc2KM7:TR?= MXrTRW5IWkWU
NCI-H1703 MYHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MoTzTWM2OD1{OD6wOFE{KM7:TR?= Mk\jV2FPT1KHUh?=
U-2-OS M2ezNWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 Mn3RTWM2OD1{OD61OVE2KM7:TR?= M2XFTnNCVkeURWK=
DBTRG-05MG M3;IOWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MXTJR|UxRTJ6LkW2OVEh|ryP M4T6SXNCVkeURWK=
MHH-ES-1 NH3CPYZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NYnP[ml7UUN3ME2zNU46PDFizszN NIXER|VUSU6JUlXS
HCC1419 NXnRepVnT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M363TmlEPTB;M{KuNVEyQSEQvF2= NIf6WXhUSU6JUlXS
HOP-62 M1\aPGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MkDRTWM2OD1|Mj6yO|AyKM7:TR?= M{XTZ3NCVkeURWK=
AM-38 M2OxN2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M4[yOmlEPTB;M{KuPVk{OSEQvF2= MmLvV2FPT1KHUh?=
NCI-H2009 NFnINlFIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NVTKOVdHUUN3ME2zN{41ODB5IN88US=> MYHTRW5IWkWU
EM-2 M3HJNmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NUPEW5dXUUN3ME2zN{42PTFzIN88US=> NHLuXIxUSU6JUlXS
SW1116 MmXPS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NUjxSJdvUUN3ME2zOE41QDN6IN88US=> MkHoV2FPT1KHUh?=
SK-N-AS NGH3XpZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NVXJfYl5UUN3ME2zOU4xPzF2IN88US=> MXzTRW5IWkWU
ChaGo-K-1 MY\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NWfORoJXUUN3ME2zOU43ODN{IN88US=> NGO2XpFUSU6JUlXS
RT-112 MkjiS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MofmTWM2OD1|NT65PFc6KM7:TR?= NVzaOlluW0GQR2LFVi=>
HTC-C3 MmLHS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M170fGlEPTB;M{[uNlM2PSEQvF2= MYTTRW5IWkWU
SK-NEP-1 NEDXTZlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MVHJR|UxRTN4Lk[xNFYh|ryP MoL5V2FPT1KHUh?=
LB831-BLC MljKS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M1rtdWlEPTB;M{euOlU1OSEQvF2= MoCxV2FPT1KHUh?=
CTB-1 M1Lab2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MWLJR|UxRTN6LkS1NVIh|ryP NVLXZ5prW0GQR2LFVi=>
MOLT-4 NXP5OG1QT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MojFTWM2OD1|OD64N|kyKM7:TR?= NHfZUnlUSU6JUlXS
SW756 MlTGS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MkLJTWM2OD12MD65N|g2KM7:TR?= Mm\HV2FPT1KHUh?=
CAL-72 MXrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M4H6fGlEPTB;NEKuNFMh|ryP MmfZV2FPT1KHUh?=
KNS-62 M2\veWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 Ml;KTWM2OD12Mj62Nlk3KM7:TR?= NGntdnNUSU6JUlXS
KARPAS-299 MVzHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NWnncm1RUUN3ME20N{4{OjN|IN88US=> NYr5TIVZW0GQR2LFVi=>
HEL Mo\2S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MmPuTWM2OD12NT60OlQ3KM7:TR?= NUGwNG1VW0GQR2LFVi=>
KP-4 M3XNcmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NVr3[ml4UUN3ME20Ok44OzZzIN88US=> NYjXS3V5W0GQR2LFVi=>
NEC8 NH3URXhIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NEnWWJBKSzVyPUS3MlE3PjFizszN MXHTRW5IWkWU
G-402 NXrISmNHT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NEXwTGhKSzVyPUS4MlcxOTJizszN NEPxfllUSU6JUlXS

... Click to View More Cell Line Experimental Data

In vivo試験 BIRB 796 (30 mg/kg) inhibits 84% of TNF-α in LPS-stimulated mice and demonstrates efficacy in a mouse model of established collagen-induced arthritis. [1] BIRB 796 has good pharmacokinetic performance even after oral administration in mice. [2]
臨床試験 Boehringer Ingelheim has announced the discontinuation of BIRB 796 R&D project in 2005.
特集 The first p38 MAPK inhibitor to be tested in a phase III clinical trial.

プロトコル (参考用のみ)

キナーゼアッセイ:

[6]

Procedures for the THP-1 cellular assay for inhibition of LPS-stimulated TNF-α production THP-1 cells are preincubated in the presence and absence of BIRB 796 for 30 min. Cell mixture is stimulated with LPS (1 μg/mL final) and incubation continued overnight (18−24 hours) as above. Supernatant is analyzed for human TNF-α by a commercially available ELISA. Data are combined and analyzed by nonlinear regression using a three parameter logistic model to obtain an EC50 value. BIRB 796 is analyzed in each experiment and the 95% confidence intervals for the EC50 are between 16 and 22 nM.

動物実験:

[2]

動物モデル Collagen-induced arthritis in female Balb/c mice
製剤 70% PEG400 (intravenous) or 100% PEG400 (oral)
投薬量 1 mg/kg (intravenous) or 10 mg/kg (oral)
投与方法 Intravenous injection or by oral

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download BIRB 796 (Doramapimod) SDF
分子量 527.66
化学式

C31H37N5O3

CAS No. 285983-48-4
保管 2年-20℃
6月-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 106 mg/mL (200.88 mM)
エタノール 106 mg/mL (200.88 mM)
<1 mg/mL (<1 mM)
In vivo 30% PEG400+0.5% Tween80+5% propylene glycol 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
化学名 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(4-(2-morpholinoethoxy)naphthalen-1-yl)urea

文献中の引用 (17)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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