Doramapimod (BIRB 796) 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
  • Doramapimod (BIRB 796)のメカニズム

製品の説明

生物活性

製品説明 Doramapimod (BIRB 796)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 MlfIS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NFzB[VNKSzVyPUCuN|Q4PjNizszN MY\TRW5IWkWU
DU-145 NY\jN2k{T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MWXJR|UxRTNwOUO4NVEh|ryP NIW5SnlUSU6JUlXS
GOTO MnrOS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MVLJR|UxRTZwM{mxOlEh|ryP MnfvV2FPT1KHUh?=
NCI-H358 NEDSTXNIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MkmzTWM2OD15LkWzPEDPxE1? MX3TRW5IWkWU
IST-MES1 MXrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NWnkNVJvUUN3ME23Mlk2PjN5IN88US=> M1XTOXNCVkeURWK=
KP-N-YN NUjld4duT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NFTL[pJKSzVyPUiuNlAyQSEQvF2= NGXIWXFUSU6JUlXS
T-24 NVvjUmVuT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MmTaTWM2OD16LkSwOlc{KM7:TR?= M12wPHNCVkeURWK=
MPP-89 M{PxNmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M3nI[mlEPTB;OD60OlI2OSEQvF2= NXracmJkW0GQR2LFVi=>
NCI-SNU-1 MYPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M1;WV2lEPTB;OT6wOlc{QSEQvF2= MUHTRW5IWkWU
BFTC-905 MXPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MoPoTWM2OD1zMD6xNlM{KM7:TR?= M4TNSHNCVkeURWK=
MS-1 MmTFS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MW\JR|UxRTFyLkiyN|Uh|ryP MknrV2FPT1KHUh?=
NBsusSR NF;IbHRIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MX7JR|UxRTFyLkiyN|Uh|ryP NVTySIRsW0GQR2LFVi=>
BEN M{Prbmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MnTCTWM2OD1zMz6xNlY1KM7:TR?= MWrTRW5IWkWU
HMV-II MUXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MV\JR|UxRTF2LkKzNFkh|ryP NHLaRpBUSU6JUlXS
NCI-H1581 NIjFdGxIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NGXBUFBKSzVyPUG3MlA1PDdizszN NFnhdHhUSU6JUlXS
ES8 MXrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NGjW[oNKSzVyPUG3MlE3PyEQvF2= NGTjUVlUSU6JUlXS
LC-2-ad MXLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M4XPb2lEPTB;MUeuOFM3PiEQvF2= M330S3NCVkeURWK=
EW-13 NVu3XYl[T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M{XiWmlEPTB;MUeuPVUyPiEQvF2= MmKwV2FPT1KHUh?=
AN3-CA MnfnS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NG\NXlVKSzVyPUG4MlEh|ryP NGDnfldUSU6JUlXS
DB NIq1fGNIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MYjJR|UxRTF6Lke5NlMh|ryP Mlu0V2FPT1KHUh?=
SK-MEL-1 MnnWS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NGfQUIpKSzVyPUKwMlM3QDNizszN NVLEeYQxW0GQR2LFVi=>
CAPAN-1 NIW3bmlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M1HsUWlEPTB;MkKuNVg5PCEQvF2= M3zoW3NCVkeURWK=
NCI-H2228 M1\PUmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M2XUT2lEPTB;MkOuOlY3QCEQvF2= MXHTRW5IWkWU
HOP-92 NYfwcpFmT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NWLZRod5UUN3ME2yOE4{QDN6IN88US=> NFrve5NUSU6JUlXS
KYSE-270 NYTHTY9wT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1HjXmlEPTB;MkSuOVU4OyEQvF2= NV3NOJprW0GQR2LFVi=>
HCC1806 NVLVSoN6T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NEfx[4tKSzVyPUK0Mlc4QTlizszN MlfQV2FPT1KHUh?=
HuO-3N1 NV[2VlZ{T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NVvNeItMUUN3ME2yOU45OTh3IN88US=> M2njNnNCVkeURWK=
HOS NYC5bndtT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= Mn3DTWM2OD1{NT65NlkzKM7:TR?= M{jnUHNCVkeURWK=
KYSE-510 MUPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NX\O[5RGUUN3ME2yOk4yPjF{IN88US=> NHvRb3FUSU6JUlXS
COLO-741 NVewW4VJT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= Mk\JTWM2OD1{Nj6zN|I6KM7:TR?= NYO3ZopHW0GQR2LFVi=>
H-EMC-SS NEfTTXhIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MVvJR|UxRTJ4LkmyOFUh|ryP NIXUbJZUSU6JUlXS
HCC1937 MXjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NHrTXJFKSzVyPUK3MlIzOzhizszN NWn5XVNxW0GQR2LFVi=>
NCI-H2126 MmLpS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MkjqTWM2OD1{Nz6zPVc2KM7:TR?= NFnL[|RUSU6JUlXS
NCI-H1703 NYTLd2huT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MWLJR|UxRTJ6LkC0NVMh|ryP NGfhbnlUSU6JUlXS
U-2-OS NF7oU45Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NG\BbVRKSzVyPUK4MlU2OTVizszN Mni0V2FPT1KHUh?=
DBTRG-05MG MXrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NUnYOXRPUUN3ME2yPE42PjVzIN88US=> NX7hZoVpW0GQR2LFVi=>
MHH-ES-1 MXzHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M3zMOmlEPTB;M{GuPVQyKM7:TR?= M4LsN3NCVkeURWK=
HCC1419 MYTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M3v2UWlEPTB;M{KuNVEyQSEQvF2= MUfTRW5IWkWU
HOP-62 MYDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NVP6N5ZwUUN3ME2zNk4zPzBzIN88US=> NGju[nJUSU6JUlXS
AM-38 M2fJUmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MY\JR|UxRTN{Lkm5N|Eh|ryP MljHV2FPT1KHUh?=
NCI-H2009 MV3Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NVrRcZJHUUN3ME2zN{41ODB5IN88US=> NVHJUpJmW0GQR2LFVi=>
EM-2 M1vLRWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MlTRTWM2OD1|Mz61OVEyKM7:TR?= Mmj0V2FPT1KHUh?=
SW1116 MVrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NFjmVYpKSzVyPUO0MlQ5OzhizszN NWP2VIdJW0GQR2LFVi=>
SK-N-AS MXvHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NXf4enpxUUN3ME2zOU4xPzF2IN88US=> MXnTRW5IWkWU
ChaGo-K-1 M1fSOmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NUC4PXBCUUN3ME2zOU43ODN{IN88US=> MWfTRW5IWkWU
RT-112 MlntS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NWX0cG12UUN3ME2zOU46QDd7IN88US=> NHTuXJBUSU6JUlXS
HTC-C3 MV;Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NGGwS|RKSzVyPUO2MlI{PTVizszN NGf0e5ZUSU6JUlXS
SK-NEP-1 MknSS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NGjQNXFKSzVyPUO2MlYyODZizszN NYDmRY5xW0GQR2LFVi=>
LB831-BLC NFL6ZZNIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NXLyUmlIUUN3ME2zO{43PTRzIN88US=> MkXCV2FPT1KHUh?=
CTB-1 M372TWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M1Pab2lEPTB;M{iuOFUyOiEQvF2= M1PNRXNCVkeURWK=
MOLT-4 MXTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MWXJR|UxRTN6LkizPVEh|ryP NFjjSnRUSU6JUlXS
SW756 MXXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MXfJR|UxRTRyLkmzPFUh|ryP NIf5XIFUSU6JUlXS
CAL-72 NFnGbZZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M2DrbmlEPTB;NEKuNFMh|ryP M3[4fnNCVkeURWK=
KNS-62 NEK0S45Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NVnUOVdDUUN3ME20Nk43Ojl4IN88US=> MmLUV2FPT1KHUh?=
KARPAS-299 M1rNOmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NFqyPHhKSzVyPUSzMlMzOzNizszN MmnRV2FPT1KHUh?=
HEL NUjzfGRvT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MYXJR|UxRTR3LkS2OFYh|ryP MUjTRW5IWkWU
KP-4 MYHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M171VGlEPTB;NE[uO|M3OSEQvF2= NWfzPFhjW0GQR2LFVi=>
NEC8 NH7aSWZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MkXVTWM2OD12Nz6xOlYyKM7:TR?= MWPTRW5IWkWU
G-402 M2rKNGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M1jnTWlEPTB;NEiuO|AyOiEQvF2= NWHFUGpVW0GQR2LFVi=>

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

C31H37N5O3

CAS No. 285983-48-4
保管 3年-20℃
2年-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 106 mg/mL (200.88 mM)
Ethanol 106 mg/mL (200.88 mM)
Water <1 mg/mL
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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