449811-01-2

Basic information

• Product Name: PAMAPIMOD
• Synonyms: PAMAPIMOD;6-(2,4-Difluorophenoxy)-2-[[3-hydroxy-1-(2-hydroxyethyl)propyl]aMino]-8-Methylpyrido[2,3-d]pyriMidin-7(8H)-one;R 1503;Ro 4402257;Pamapimod (R-1503);Pamapimod (R-1503, Ro4402257)
• CAS NO: 449811-01-2
• Molecular Formula: C₁₉H₂₀F₂N₄O₄
• Molecular Weight: 406.3833064
• Product Categories: Amines;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 449811-01-2.mol
• Article Data: 1

Chemical Properties

• Appearance: /
• Storage Temp.: -20°C Freezer
• Solubility: DMSO (Slightly), Methanol (Slightly)
• CAS DataBase Reference: PAMAPIMOD(CAS DataBase Reference)
• NIST Chemistry Reference: PAMAPIMOD(449811-01-2)
• EPA Substance Registry System: PAMAPIMOD(449811-01-2)

Safety Data

• Hazardous Substances Data: 449811-01-2(Hazardous Substances Data)

Usage

Description

PAMAPIMOD, also known as 8-methylpyrido[2,3-d]pyrimidin-7(8H)-one, is a member of the pyridopyrimidines class. It is characterized by additional (1,5-dihydroxypentan-3-yl)amino and 2,4-difluorophenoxy substituents at positions 2 and 6, respectively. PAMAPIMOD is a potent inhibitor of MAPK and has been investigated for its potential therapeutic applications.

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).

Upstream product

• 185040-32-8 4-methylamino-2-methylthiopyrimidine-5-carboxaldehyde 
• 76360-82-2 4-methylamino-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester 
• 77313-09-8 3-aminoglutaric acid dimethyl ester 
• 1117-23-3 3-aminopentane-1,5-diol 
• 5909-24-0 4-chloro-2-methanesulfanylpyrimidine-5-carboxylic acid ethyl ester 
• 17759-30-7 (4-methylamino-2-methylsulfanyl-pyrimidin-5-yl)-methanol 
• 449811-12-5 6?(2,4?difluorophenoxy)?8?methyl?2?(methylthio)pyrido[2,3?d]pyrimidin?7(8H)?one 
• 449808-50-8 6-(2,4-difluorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one 
• 1032451-78-7 3-trimethylsilanyloxy-1-(2-trimethylsilanyloxyethyl)propylamine 

Relevant 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

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.