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Pamapimod

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Chemical Structure| 449811-01-2 同义名 : R1503;Ro4402257
CAS号 : 449811-01-2
货号 : A628708
分子式 : C19H20F2N4O4
纯度 : 98%+
分子量 : 406.383
MDL号 : MFCD25976551
存储条件：

粉末 Keep in dark place,Inert atmosphere,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 35 mg/mL(86.13 mM)，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：
生物活性
靶点

  • p38β

    p38β, IC50:0.48 μM

  • p38α

    p38α, IC50:0.014 μM
描述 The family members of the mitogen-activated protein kinase (MAPK) mediate a wide variety of cellular behaviors in response to extracellular stimuli. One of the four main sub-groups, the p38 group of MAP kinases, serve as a nexus for signal transduction and play a vital role in numerous biological processes[3]. Pamapimod inhibited p38α and p38β enzymatic activity, with IC50 values of 0.014 ± 0.002 and 0.48 ± 0.04 μM, respectively[4]. Pamapimod inhibited p38 (IC50, 0.06 μM), but inhibition of c-Jun NH(2)-terminal kinase (JNK) was not detected. Pamapimod also inhibited lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF)-α production by monocytes, interleukin (IL)-1β production in human whole blood, and spontaneous TNFα production by synovial explants from rheumatoid arthritis (RA) patients[4]. Intravenous systemic clearance of pamapimod was low to moderate across species pamapimod was well absorbed and had high oral bioavailability in the rat, monkey, and dog (62%-80%)[5]. LPS- and TNFα-stimulated production of TNFα and IL-6 in rodents also was inhibited by pamapimod. In murine collagen-induced arthritis, pamapimod reduced clinical signs of inflammation and bone loss at 50 mg/kg or greater. In a rat model of hyperalgesia, pamapimod increased tolerance to pressure in a dose-dependent manner, suggesting an important role of p38 in pain associated with inflammation[4]. we treated ovariectomized (OVX) mice with pamapimod and revealed a protective effect of pamapimod on osteoporosis in vivo[6].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.46mL

0.49mL

0.25mL

12.30mL

2.46mL

1.23mL

24.61mL

4.92mL

2.46mL
参考文献

[1]Alten RE, Zerbini C, et al. Efficacy and safety of pamapimod in patients with active rheumatoid arthritis receiving stable methotrexate therapy. Ann Rheum Dis. 2010 Feb;69(2):364-7.

[2]Doggrell SA, Christensen AM. Does the p38 MAP kinase inhibitor pamapimod have potential for the treatment of rheumatoid arthritis? Expert Opin Pharmacother. 2010 Oct;11(14):2437-42.

[3]Zarubin T, Han J. Activation and signaling of the p38 MAP kinase pathway. Cell Res. 2005 Jan;15(1):11-8. doi: 10.1038/sj.cr.7290257. PMID: 15686620.

[4]Hill RJ, Dabbagh K, Phippard D, Li C, Suttmann RT, Welch M, Papp E, Song KW, Chang KC, Leaffer D, Kim YN, Roberts RT, Zabka TS, Aud D, Dal Porto J, Manning AM, Peng SL, Goldstein DM, Wong BR. Pamapimod, a novel p38 mitogen-activated protein kinase inhibitor: preclinical analysis of efficacy and selectivity. J Pharmacol Exp Ther. 2008 Dec;327(3):610-9. doi: 10.1124/jpet.108.139006. Epub 2008 Sep 5. PMID: 18776065.

[5]Goldstein DM, Soth M, Gabriel T, Dewdney N, Kuglstatter A, Arzeno H, Chen J, Bingenheimer W, Dalrymple SA, Dunn J, Farrell R, Frauchiger S, La Fargue J, Ghate M, Graves B, Hill RJ, Li F, Litman R, Loe B, McIntosh J, McWeeney D, Papp E, Park J, Reese HF, Roberts RT, Rotstein D, San Pablo B, Sarma K, Stahl M, Sung ML, Suttman RT, Sjogren EB, Tan Y, Trejo A, Welch M, Weller P, Wong BR, Zecic H. Discovery of 6-(2,4-difluorophenoxy)-2-[3-hydroxy-1-(2-hydroxyethyl)propylamino]-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (pamapimod) and 6-(2,4-difluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (R1487) as orally bioavailable and highly selective inhibitors of p38α mitogen-activated protein kinase. J Med Chem. 2011 Apr 14;54(7):2255-65. doi: 10.1021/jm101423y. Epub 2011 Mar 4. PMID: 21375264.

[6]Zhao X, Ning L, Xie Z, Jie Z, Li X, Wan X, Sun X, Huang B, Tang P, Shen S, Qin A, Ma Y, Song L, Fan S, Wan S. The Novel p38 Inhibitor, Pamapimod, Inhibits Osteoclastogenesis and Counteracts Estrogen-Dependent Bone Loss in Mice. J Bone Miner Res. 2019 May;34(5):911-922. doi: 10.1002/jbmr.3655. Epub 2019 Jan 7. Erratum in: J Bone Miner Res. 2020 Aug;35(8):1618-1619. PMID: 30615802.