449811-01-2 Usage
Uses
Used in Pharmaceutical Industry:
PAMAPIMOD is used as a selective inhibitor of the α-isoform of p38 MAP kinase for the treatment of patients with rheumatoid arthritis. Although it was found to be tolerable, it was not as effective as Methotrexate in clinical trials. Its role as a potent inhibitor of MAPK makes it a valuable compound for further research and development in the treatment of various diseases and conditions related to the activation of this kinase.
Biological Activity
pamapimod (r-1503, ro4402257) is a p38 mapk inhibitor.p38alpha, a protein kinase, regulates the inflammatory cytokine expression, indicating a key role in the pathogenesis of diseases such as rheumatoid arthritis and systemic lupus erythematosus.
in vitro
pamapimod could inhibit p38alpha and p38beta enzymatic activity, and there was no activity against p38delta or p38gamma. when profiled across 350 kinases, pamapimod bound only to four kinases. moreover, pamapimod was found to inhibit p38, but jnk inhibition was not detected. pamapimod also inhibited lps-stimulated tnfα production by monocytes, il-1β production. in addition, lps- and tnfα-stimulated production of tnfα and il-6 in rodent plasma could be also inhibited by pamapimod [1].
in vivo
in murine collagen-induced arthritis, pamapimod was able to reduce the clinical signs of inflammation and bone loss at 50 mg/kg or greater. moreover, pamapimod dose-dependently increased the tolerance pressure in a rat model of hyperalgesia, indicating the critical role of p38 in pain associated with inflammation. furthermore, a pamapimod analog had equivalent potency and selectivity in lupus-prone mrl/lpr mice [1].
IC 50
0.014 and 0.48 μm for p38α and p38β enzymatic activity, respectively.
references
[1] hill, r. j. et al. pamapimod, a novel p38 mitogen-activated protein kinase inhibitor: preclinical analysis of efficacy and selectivity. the journal of pharmacology and experimental therapeutics 327, 610-619, doi:10.1124/jpet.108.139006 (2008).
Check Digit Verification of cas no
The CAS Registry Mumber 449811-01-2 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 4,4,9,8,1 and 1 respectively; the second part has 2 digits, 0 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 449811-01:
(8*4)+(7*4)+(6*9)+(5*8)+(4*1)+(3*1)+(2*0)+(1*1)=162
162 % 10 = 2
So 449811-01-2 is a valid CAS Registry Number.
449811-01-2Relevant articles and documents
Discovery of 6-(2,4-difluorophenoxy)-2-[3-hydroxy-1-(2-hydroxyethyl) propylamino]-8-methyl-8 H -pyrido[2,3- d ]pyrimidin-7-one (pamapimod) and 6-(2,4-difluorophenoxy)-8-methyl-2-(tetrahydro-2 H -pyran-4-ylamino)pyrido[2,3- d ]pyrimidin-7(8 H)-one (R1487) as orally bioavailable and highly selective inhibitors of p38α mitogen-activated protein kinase
Goldstein, David M.,Soth, Michael,Gabriel, Tobias,Dewdney, Nolan,Kuglstatter, Andreas,Arzeno, Humberto,Chen, Jeffrey,Bingenheimer, William,Dalrymple, Stacie A.,Dunn, James,Farrell, Robert,Frauchiger, Sandra,La Fargue, Joann,Ghate, Manjiri,Graves, Bradford,Hill, Ronald J.,Li, Fujun,Litman, Renee,Loe, Brad,McIntosh, Joel,McWeeney, Daniel,Papp, Eva,Park, Jaehyeon,Reese, Harlan F.,Roberts, Richard T.,Rotstein, David,San Pablo, Bong,Sarma, Keshab,Stahl, Martin,Sung, Man-Ling,Suttman, Rebecca T.,Sjogren, Eric B.,Tan, Yunchou,Trejo, Alejandra,Welch, Mary,Weller, Paul,Wong, Brian R.,Zecic, Hasim
, p. 2255 - 2265 (2011/06/21)
The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.
