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 MXTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? Mnz2TWM2OD1yLkO0O|Y{KM7:TR?= M{PlT3NCVkeURWK=
DU-145 M1TnVGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NH3n[2dKSzVyPUOuPVM5OTFizszN NHPoN5FUSU6JUlXS
GOTO MoX0S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NHnQe|FKSzVyPU[uN|kyPjFizszN MknRV2FPT1KHUh?=
NCI-H358 NHrGUYRIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MlHXTWM2OD15LkWzPEDPxE1? MoGyV2FPT1KHUh?=
IST-MES1 NGq2eJVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NVrIbGtpUUN3ME23Mlk2PjN5IN88US=> NVHTR5dEW0GQR2LFVi=>
KP-N-YN M3;iNWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M{C1ZmlEPTB;OD6yNFE6KM7:TR?= M3n1bXNCVkeURWK=
T-24 M1Pkd2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MU\JR|UxRThwNEC2O|Mh|ryP MWPTRW5IWkWU
MPP-89 NUP4b4doT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M3OySGlEPTB;OD60OlI2OSEQvF2= MYnTRW5IWkWU
NCI-SNU-1 MWPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MmHPTWM2OD17LkC2O|M6KM7:TR?= NVLpNHlOW0GQR2LFVi=>
BFTC-905 MWjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NUjBXpNOUUN3ME2xNE4yOjN|IN88US=> NVvvPIZVW0GQR2LFVi=>
MS-1 MnrNS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M4LvbmlEPTB;MUCuPFI{PSEQvF2= MVvTRW5IWkWU
NBsusSR MWrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NXHDe4R[UUN3ME2xNE45OjN3IN88US=> NFzBbXBUSU6JUlXS
BEN NXnrSGJnT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M2jOZWlEPTB;MUOuNVI3PCEQvF2= M4e1XXNCVkeURWK=
HMV-II Mm\iS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M3;VOWlEPTB;MUSuNlMxQSEQvF2= NX[3d4tlW0GQR2LFVi=>
NCI-H1581 NYC1T2NTT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NWfaU5hwUUN3ME2xO{4xPDR5IN88US=> NXXYdVZWW0GQR2LFVi=>
ES8 NU\OVoQ3T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MX\JR|UxRTF5LkG2O{DPxE1? Mnn6V2FPT1KHUh?=
LC-2-ad M4P6dWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M2OxV2lEPTB;MUeuOFM3PiEQvF2= NIThRo5USU6JUlXS
EW-13 M37uVGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NH61cGRKSzVyPUG3Mlk2OTZizszN NHPHVoZUSU6JUlXS
AN3-CA MWDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NVPTcIR{UUN3ME2xPE4yKM7:TR?= MV\TRW5IWkWU
DB NIPXT|VIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NGniS3VKSzVyPUG4Mlc6OjNizszN M3vNT3NCVkeURWK=
SK-MEL-1 NWDVZ4trT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M{PD[WlEPTB;MkCuN|Y5OyEQvF2= NHTVTYhUSU6JUlXS
CAPAN-1 MUDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M1XIeGlEPTB;MkKuNVg5PCEQvF2= MU\TRW5IWkWU
NCI-H2228 MmXZS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MYHJR|UxRTJ|Lk[2Olgh|ryP NE\MeGhUSU6JUlXS
HOP-92 MnKwS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MnHyTWM2OD1{ND6zPFM5KM7:TR?= NXO2foRKW0GQR2LFVi=>
KYSE-270 NYPBc|cyT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NGrQWIdKSzVyPUK0MlU2PzNizszN NIj6d5lUSU6JUlXS
HCC1806 NUPuTmRLT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NETZdWFKSzVyPUK0Mlc4QTlizszN NIOwV5hUSU6JUlXS
HuO-3N1 MoG3S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NWjhRnViUUN3ME2yOU45OTh3IN88US=> NIXMZYlUSU6JUlXS
HOS NFOyWFNIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NFXOU5VKSzVyPUK1MlkzQTJizszN NHTOWlZUSU6JUlXS
KYSE-510 NGriZlhIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NHWyNWZKSzVyPUK2MlE3OTJizszN MVvTRW5IWkWU
COLO-741 NWr2RYtlT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NITLOYxKSzVyPUK2MlM{OjlizszN NE\sVXZUSU6JUlXS
H-EMC-SS NV;rV4RsT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NVjndYxUUUN3ME2yOk46OjR3IN88US=> NI\lXXlUSU6JUlXS
HCC1937 MmrzS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MkDYTWM2OD1{Nz6yNlM5KM7:TR?= NESzO4FUSU6JUlXS
NCI-H2126 MWPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NEHoc2FKSzVyPUK3MlM6PzVizszN MYLTRW5IWkWU
NCI-H1703 M1nDW2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MYjJR|UxRTJ6LkC0NVMh|ryP MX3TRW5IWkWU
U-2-OS M2nMWGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NXjhdXhRUUN3ME2yPE42PTF3IN88US=> M{POXHNCVkeURWK=
DBTRG-05MG MYDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NWCyfFVyUUN3ME2yPE42PjVzIN88US=> MmrGV2FPT1KHUh?=
MHH-ES-1 NFHLRpFIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MmfsTWM2OD1|MT65OFEh|ryP M3zXe3NCVkeURWK=
HCC1419 NVn3UppxT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MWLJR|UxRTN{LkGxNVkh|ryP MV3TRW5IWkWU
HOP-62 NVzmd4hGT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NET4elNKSzVyPUOyMlI4ODFizszN MnnoV2FPT1KHUh?=
AM-38 M3jWU2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NE[4R|hKSzVyPUOyMlk6OzFizszN MYnTRW5IWkWU
NCI-H2009 NIrmRVVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NV23VpB2UUN3ME2zN{41ODB5IN88US=> M3G3bXNCVkeURWK=
EM-2 MmXSS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NFPBNmlKSzVyPUOzMlU2OTFizszN NXzQfJdMW0GQR2LFVi=>
SW1116 NHrqWXRIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NIi4OXBKSzVyPUO0MlQ5OzhizszN NUWwR45tW0GQR2LFVi=>
SK-N-AS MV;Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NX3qS4JZUUN3ME2zOU4xPzF2IN88US=> MVjTRW5IWkWU
ChaGo-K-1 NIr5PJlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NVjaWXlFUUN3ME2zOU43ODN{IN88US=> MnvnV2FPT1KHUh?=
RT-112 M37NNmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NV\yNldQUUN3ME2zOU46QDd7IN88US=> NG[0cItUSU6JUlXS
HTC-C3 Mm\HS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M1TSZ2lEPTB;M{[uNlM2PSEQvF2= MkPuV2FPT1KHUh?=
SK-NEP-1 MVHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NVjVPGhlUUN3ME2zOk43OTB4IN88US=> NFvEVHJUSU6JUlXS
LB831-BLC MnLxS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M4H2emlEPTB;M{euOlU1OSEQvF2= NYj4Z5NLW0GQR2LFVi=>
CTB-1 NWL2[HU3T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MlrMTWM2OD1|OD60OVEzKM7:TR?= M3XF[nNCVkeURWK=
MOLT-4 NIfCO2dIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MV;JR|UxRTN6LkizPVEh|ryP NY\6b3Z5W0GQR2LFVi=>
SW756 MknsS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M2HpcmlEPTB;NECuPVM5PSEQvF2= NUnoR2RvW0GQR2LFVi=>
CAL-72 NEmzRZZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NHG0fZhKSzVyPUSyMlA{KM7:TR?= NV;ONpRyW0GQR2LFVi=>
KNS-62 MWHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MXHJR|UxRTR{Lk[yPVYh|ryP NYLxSm5yW0GQR2LFVi=>
KARPAS-299 NYrPNmNQT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MULJR|UxRTR|LkOyN|Mh|ryP M3LaTnNCVkeURWK=
HEL MlvJS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MX7JR|UxRTR3LkS2OFYh|ryP NU[yNG52W0GQR2LFVi=>
KP-4 NH;zPWVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NWLjcpZnUUN3ME20Ok44OzZzIN88US=> MWXTRW5IWkWU
NEC8 MmTSS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NF[wUYJKSzVyPUS3MlE3PjFizszN NE\xZlhUSU6JUlXS
G-402 NIK2SIJIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M4nacWlEPTB;NEiuO|AyOiEQvF2= NVvXcXFXW0GQR2LFVi=>

... 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 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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