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

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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 MX\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M{K4OmlEPTB;MD6zOFc3OyEQvF2= NFf2[JNUSU6JUlXS
DU-145 NYj6d297T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MkXpTWM2OD1|LkmzPFEyKM7:TR?= NIHlRoRUSU6JUlXS
GOTO Mo\2S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MWXJR|UxRTZwM{mxOlEh|ryP NF\UbIVUSU6JUlXS
NCI-H358 MmfzS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NFX5NXZKSzVyPUeuOVM5KM7:TR?= Mn;1V2FPT1KHUh?=
IST-MES1 M4PCTmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MnPZTWM2OD15Lkm1OlM4KM7:TR?= M37rfXNCVkeURWK=
KP-N-YN M1nnd2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MnjUTWM2OD16LkKwNVkh|ryP M3jwZXNCVkeURWK=
T-24 NIPxSZFIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M1zUeWlEPTB;OD60NFY4OyEQvF2= M4Lx[XNCVkeURWK=
MPP-89 M2P6Zmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NHTPcHFKSzVyPUiuOFYzPTFizszN MY\TRW5IWkWU
NCI-SNU-1 NInxXlRIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NVnY[pJlUUN3ME25MlA3PzN7IN88US=> MW\TRW5IWkWU
BFTC-905 MYHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NHLzRlNKSzVyPUGwMlEzOzNizszN MkXyV2FPT1KHUh?=
MS-1 MWTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NV\iNnFWUUN3ME2xNE45OjN3IN88US=> M{myTnNCVkeURWK=
NBsusSR NUTYclR3T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NGPzTFNKSzVyPUGwMlgzOzVizszN NXTNbXdvW0GQR2LFVi=>
BEN MlPiS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NW\ocJh[UUN3ME2xN{4yOjZ2IN88US=> M4DDTXNCVkeURWK=
HMV-II NVrpSHFNT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M13ZWGlEPTB;MUSuNlMxQSEQvF2= NWP4OYhCW0GQR2LFVi=>
NCI-H1581 NIrpUGxIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NXLpfWtGUUN3ME2xO{4xPDR5IN88US=> M2ewdHNCVkeURWK=
ES8 MW\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MlTOTWM2OD1zNz6xOlch|ryP NWrwe5pEW0GQR2LFVi=>
LC-2-ad NYjFbppbT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MXHJR|UxRTF5LkSzOlYh|ryP MY\TRW5IWkWU
EW-13 NH[5NZJIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MYTJR|UxRTF5Lkm1NVYh|ryP M{\ENXNCVkeURWK=
AN3-CA NYLqPG9RT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NHX6NW1KSzVyPUG4MlEh|ryP NE\6U4FUSU6JUlXS
DB NIjnNmFIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MmjzTWM2OD1zOD63PVI{KM7:TR?= NYHhZoY5W0GQR2LFVi=>
SK-MEL-1 NF\0e4hIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MXrJR|UxRTJyLkO2PFMh|ryP MWHTRW5IWkWU
CAPAN-1 NVX1bVF3T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MnfpTWM2OD1{Mj6xPFg1KM7:TR?= MUXTRW5IWkWU
NCI-H2228 NX7UWZRwT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NX[yfHVWUUN3ME2yN{43PjZ6IN88US=> NWLDRoM1W0GQR2LFVi=>
HOP-92 MkjhS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M3n6PWlEPTB;MkSuN|g{QCEQvF2= NGPOWJJUSU6JUlXS
KYSE-270 NXTxTZo4T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MlXtTWM2OD1{ND61OVc{KM7:TR?= MXjTRW5IWkWU
HCC1806 M2DVXGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NF74SWRKSzVyPUK0Mlc4QTlizszN Mn;CV2FPT1KHUh?=
HuO-3N1 MULHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NILafZVKSzVyPUK1MlgyQDVizszN MULTRW5IWkWU
HOS NWru[VA3T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MUnJR|UxRTJ3LkmyPVIh|ryP M{XOb3NCVkeURWK=
KYSE-510 M{ewS2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NVnQSpRvUUN3ME2yOk4yPjF{IN88US=> NWDMcFN5W0GQR2LFVi=>
COLO-741 M17jNGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 Mn\2TWM2OD1{Nj6zN|I6KM7:TR?= MoG2V2FPT1KHUh?=
H-EMC-SS MkfiS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NWSwbWQzUUN3ME2yOk46OjR3IN88US=> NILodWJUSU6JUlXS
HCC1937 NEO4clZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M3nY[WlEPTB;MkeuNlI{QCEQvF2= MWPTRW5IWkWU
NCI-H2126 MlLMS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M1zjdGlEPTB;MkeuN|k4PSEQvF2= M3HLOHNCVkeURWK=
NCI-H1703 MoHsS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NY\XUHRyUUN3ME2yPE4xPDF|IN88US=> MoO5V2FPT1KHUh?=
U-2-OS MmWzS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MUXJR|UxRTJ6LkW1NVUh|ryP MlHyV2FPT1KHUh?=
DBTRG-05MG NVrSO2ZmT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= Mly1TWM2OD1{OD61OlUyKM7:TR?= NXvZUYRyW0GQR2LFVi=>
MHH-ES-1 M17CfGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NH\rdHdKSzVyPUOxMlk1OSEQvF2= Mn70V2FPT1KHUh?=
HCC1419 MmfOS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NHGySFNKSzVyPUOyMlEyOTlizszN MniyV2FPT1KHUh?=
HOP-62 NH3YU3hIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MXfJR|UxRTN{LkK3NFEh|ryP M1LTXHNCVkeURWK=
AM-38 NH3zW4pIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NGC1TJNKSzVyPUOyMlk6OzFizszN NH;CbHhUSU6JUlXS
NCI-H2009 NXvV[ph5T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NEDNVYhKSzVyPUOzMlQxODdizszN MVLTRW5IWkWU
EM-2 MVfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NYPlNVhkUUN3ME2zN{42PTFzIN88US=> MVzTRW5IWkWU
SW1116 NVLScoJnT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MnTXTWM2OD1|ND60PFM5KM7:TR?= NHLINXpUSU6JUlXS
SK-N-AS MlvxS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MojNTWM2OD1|NT6wO|E1KM7:TR?= MWPTRW5IWkWU
ChaGo-K-1 Mn3XS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NGfTZlJKSzVyPUO1MlYxOzJizszN MXnTRW5IWkWU
RT-112 MkfvS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MoXvTWM2OD1|NT65PFc6KM7:TR?= MkDIV2FPT1KHUh?=
HTC-C3 NHnPRnVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NWD6dIVOUUN3ME2zOk4zOzV3IN88US=> MUfTRW5IWkWU
SK-NEP-1 NX7iWnRxT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MmXtTWM2OD1|Nj62NVA3KM7:TR?= MUnTRW5IWkWU
LB831-BLC NFvWZZBIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MVPJR|UxRTN5Lk[1OFEh|ryP NWG0bJlbW0GQR2LFVi=>
CTB-1 MXnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M2DRcGlEPTB;M{iuOFUyOiEQvF2= NF7CSYFUSU6JUlXS
MOLT-4 MXHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MmHLTWM2OD1|OD64N|kyKM7:TR?= MoLaV2FPT1KHUh?=
SW756 NGPyXIRIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NHS2RWNKSzVyPUSwMlk{QDVizszN NE\rbJJUSU6JUlXS
CAL-72 NWTWemJpT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NGnEOWRKSzVyPUSyMlA{KM7:TR?= MWTTRW5IWkWU
KNS-62 MnTWS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M2K3[mlEPTB;NEKuOlI6PiEQvF2= NWXNXVExW0GQR2LFVi=>
KARPAS-299 NHv6NndIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MlnkTWM2OD12Mz6zNlM{KM7:TR?= MljDV2FPT1KHUh?=
HEL MXzHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M1z5fmlEPTB;NEWuOFY1PiEQvF2= Ml\WV2FPT1KHUh?=
KP-4 MXfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MkLiTWM2OD12Nj63N|YyKM7:TR?= M3ux[HNCVkeURWK=
NEC8 NITIPJVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M4\yU2lEPTB;NEeuNVY3OSEQvF2= M{H5bHNCVkeURWK=
G-402 M1zzRWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MV7JR|UxRTR6LkewNVIh|ryP NFzrVGZUSU6JUlXS

... 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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