Pamapimod | R-1503 | Ro-4402257 | CAS#449811-01-2 | p38 MAPK inhibitor

MedKoo Cat#: 510233 | Name: Pamapimod

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Pamapimod is a novel p38 mitogen-activated protein kinase inhibitor. Pamapimod inhibited p38alpha and p38beta enzymatic activity, with IC(50) values of 0.014 +/- 0.002 and 0.48 +/- 0.04 microM, respectively. There was no activity against p38delta or p38gamma isoforms. When profiled across 350 kinases, pamapimod bound only to four kinases in addition to p38. Cellular potency was assessed using phosphorylation of heat shock protein-27 and c-Jun as selective readouts for p38 and c-Jun NH(2)-terminal kinase (JNK), respectively. Pamapimod inhibited p38 (IC(50), 0.06 microM), but inhibition of JNK was not detected. Pamapimod also inhibited lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) alpha production by monocytes, interleukin (IL)-1beta production in human whole blood, and spontaneous TNFalpha production by synovial explants from RA patients. Pamapimod is a potent, selective inhibitor of p38alpha with the ability to inhibit the signs and symptoms of RA and other autoimmune diseases. (copied from J Pharmacol Exp Ther. 2008 Dec;327(3):610-9.)

Chemical Structure

Pamapimod

CAS#449811-01-2

Theoretical Analysis

MedKoo Cat#: 510233

Name: Pamapimod

CAS#: 449811-01-2

Chemical Formula: C19H20F2N4O4

Exact Mass: 406.1453

Molecular Weight: 406.39

Elemental Analysis: C, 56.15; H, 4.96; F, 9.35; N, 13.79; O, 15.75

Price and Availability

Size	Price	Availability
5mg	USD 250.00	2 Weeks
10mg	USD 450.00	2 Weeks
25mg	USD 950.00	2 Weeks

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Related CAS #

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Synonym

Pamapimod; R 1503; R1503; R-1503; Ro 4402257; Ro4402257; Ro-4402257.

IUPAC/Chemical Name

6-(2,4-Difluorophenoxy)-2-[[3-hydroxy-1-(2-hydroxyethyl)propyl]amino]-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

InChi Key

JYYLVUFNAHSSFE-UHFFFAOYSA-N

InChi Code

InChI=1S/C19H20F2N4O4/c1-25-17-11(10-22-19(24-17)23-13(4-6-26)5-7-27)8-16(18(25)28)29-15-3-2-12(20)9-14(15)21/h2-3,8-10,13,26-27H,4-7H2,1H3,(H,22,23,24)

SMILES Code

O=C1C(OC2=CC=C(F)C=C2F)=CC3=CN=C(NC(CCO)CCO)N=C3N1C

Appearance

white solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Instruction

View handling instruction

Biological target:

Pamapimod (Ro4402257) is a potent, selective and orally active p38 MAPK inhibitor with IC50s of 14 nM and 480 nM and Kis of 1.3 nM and 120 nM for p38α and p38β.

In vitro activity:

This study focused on a p38 inhibitor named Pamapimod (PAM) in the effect of CH hypertrophy degeneration. PAM treatments significantly inhibited p-p38 and MEF2C expression, down-regulated type X collagen, MMP-13, and Runx-2 expression and upregulated type II collagen and SOX-9 levels. PAM indirectly affected MEF2C expression and resulted in CHs hypertrophy suppression. Reference: Panminerva Med. 2020 Dec 2. https://pubmed.ncbi.nlm.nih.gov/33263251/

In vivo activity:

OVX-induced mouse osteoporosis model was utilized to investigate the effects of PAM (pamapimod) treatment on osteoporosis. Compared with the vehicle-treated group, there was an increase in the values of BV/TV, Tb.Th, and Tb.N but a decrease of BS/BV and Tb.Sp in the PAM-treated group in a dose-dependent manner (Fig. 5A, B). Hematoxylin and eosin (H&E) staining further verified the beneficial effect of PAM to the bone mass of OVX mice (Fig. 5C). The protective effects of PAM could be further confirmed as both the number of multinucleated osteoclasts and Oc.S/BS% declined in the PAM-treated group compared with the vehicle-treated group (Fig. 5C, D). Reference: J Bone Miner Res. 2019 May;34(5):911-922. https://pubmed.ncbi.nlm.nih.gov/30615802/

	Solvent	mg/mL	mM
Solubility
	DMF	30.0	73.82
	DMSO	48.0	118.93
	DMSO:PBS (pH 7.2) (1:3)	0.3	0.62
	Ethanol	14.2	34.86

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 406.39 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Zhang J, Yan C, He W, Wang M, Liu J. Inhibition against p38/MEF2C pathway by Pamapimod protects osteoarthritis chondrocytes hypertrophy. Panminerva Med. 2020 Dec 2. doi: 10.23736/S0031-0808.20.04170-1. Epub ahead of print. PMID: 33263251. 2. 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. 3. 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.

In vitro protocol:

In vivo protocol:

1. 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. 2. 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.

1: Fumeaux T, Berger C, Bausch A, Wright M, Vilimanovich U, Soldatovic I, Vehreschild MJGT. The KINETIC phase 2 randomized controlled trial of oral pamapimod-pioglitazone in non-critically ill COVID-19 inpatients. iScience. 2023 Sep 27;26(10):108038. doi: 10.1016/j.isci.2023.108038. PMID: 37876609; PMCID: PMC10590811. 2: Setz C, Große M, Auth J, Fröba M, Rauch P, Bausch A, Wright M, Schubert U. Synergistic Antiviral Activity of Pamapimod and Pioglitazone against SARS-CoV-2 and Its Variants of Concern. Int J Mol Sci. 2022 Jun 20;23(12):6830. doi: 10.3390/ijms23126830. PMID: 35743273; PMCID: PMC9224751. 3: Sonkar C, Doharey PK, Rathore AS, Singh V, Kashyap D, Sahoo AK, Mittal N, Sharma B, Jha HC. Repurposing of gastric cancer drugs against COVID-19. Comput Biol Med. 2021 Oct;137:104826. doi: 10.1016/j.compbiomed.2021.104826. Epub 2021 Sep 6. PMID: 34537409; PMCID: PMC8420180. 4: Zhang J, Yan C, He W, Wang M, Liu J. Inhibition against p38/MEF2C pathway by Pamapimod protects osteoarthritis chondrocytes hypertrophy. Panminerva Med. 2020 Dec 2. doi: 10.23736/S0031-0808.20.04170-1. Epub ahead of print. PMID: 33263251. 5: 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. 2020 Aug;35(8):1618-1619. doi: 10.1002/jbmr.4095. Epub 2020 Jun 17. Erratum for: J Bone Miner Res. 2019 May;34(5):911-922. doi: 10.1002/jbmr.3655. PMID: 32790168. 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. doi: 10.1002/jbmr.4095. PMID: 30615802. 7: Fehr S, Unger A, Schaeffeler E, Herrmann S, Laufer S, Schwab M, Albrecht W. Impact of p38 MAP Kinase Inhibitors on LPS-Induced Release of TNF-α in Whole Blood and Primary Cells from Different Species. Cell Physiol Biochem. 2015;36(6):2237-49. doi: 10.1159/000430188. Epub 2015 Jul 24. PMID: 26279429. 8: Zhang X, Fettner S, Winter E, Masjedizadeh M, Hisoire G. Metabolism and excretion of a novel p38 MAP kinase inhibitor pamapimod in healthy male subjects. Int J Clin Pharmacol Ther. 2011 Jun;49(6):345-52. doi: 10.5414/cp201530. PMID: 21612741. 9: 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. 10: 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. doi: 10.1517/14656566.2010.507631. PMID: 20666701. 11: Joos H, Albrecht W, Laufer S, Brenner RE. Differential effects of p38MAP kinase inhibitors on the expression of inflammation-associated genes in primary, interleukin-1beta-stimulated human chondrocytes. Br J Pharmacol. 2010 Jul;160(5):1252-62. doi: 10.1111/j.1476-5381.2010.00760.x. PMID: 20590617; PMCID: PMC2936033. 12: Cohen S, Fleischmann R. Kinase inhibitors: a new approach to rheumatoid arthritis treatment. Curr Opin Rheumatol. 2010 May;22(3):330-5. doi: 10.1097/BOR.0b013e3283378e6f. PMID: 20164774. 13: Zhang X, Huang Y, Navarro MT, Hisoire G, Caulfield JP. A proof-of-concept and drug-drug interaction study of pamapimod, a novel p38 MAP kinase inhibitor, with methotrexate in patients with rheumatoid arthritis. J Clin Pharmacol. 2010 Sep;50(9):1031-8. doi: 10.1177/0091270009357433. Epub 2010 Jan 25. PMID: 20100913. 14: Goldstein DM, Kuglstatter A, Lou Y, Soth MJ. Selective p38alpha inhibitors clinically evaluated for the treatment of chronic inflammatory disorders. J Med Chem. 2010 Mar 25;53(6):2345-53. doi: 10.1021/jm9012906. PMID: 19950901. 15: Alten RE, Zerbini C, Jeka S, Irazoque F, Khatib F, Emery P, Bertasso A, Rabbia M, Caulfield JP. Efficacy and safety of pamapimod in patients with active rheumatoid arthritis receiving stable methotrexate therapy. Ann Rheum Dis. 2010 Feb;69(2):364-7. doi: 10.1136/ard.2008.104802. Epub 2009 Apr 8. Erratum in: Ann Rheum Dis. 2011 Aug;70(8):1519. PMID: 19357113. 16: Cohen SB, Cheng TT, Chindalore V, Damjanov N, Burgos-Vargas R, Delora P, Zimany K, Travers H, Caulfield JP. Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double-blind, methotrexate- controlled study of patients with active rheumatoid arthritis. Arthritis Rheum. 2009 Feb;60(2):335-44. doi: 10.1002/art.24266. PMID: 19180516. 17: Genovese MC. Inhibition of p38: has the fat lady sung? Arthritis Rheum. 2009 Feb;60(2):317-20. doi: 10.1002/art.24264. PMID: 19180514. 18: 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.