Target Validation Information
Target ID T65864
Target Name Mitogen-activated protein kinase 14
Target Type
Clinical Trial
Drug Potency against Target RWJ-68354 Drug Info IC50 = 1500 nM [526530]
IN-1166 Drug Info IC50 = 1030 nM [529552]
Phenyl-(3-phenyl-1H-indazol-6-yl)-amine Drug Info IC50 = 30 nM [527722]
6-o-tolylquinazolin-2-amine Drug Info IC50 = 3903 nM [528429]
ML-3403 Drug Info IC50 = 990 nM [526668]
GW-788388 Drug Info IC50 = 7280 nM [528108]
PD-0166326 Drug Info IC50 = 140 nM [530497]
PD-0173956 Drug Info IC50 = 50 nM [530497]
N-(4-fluorobenzyl)-N-(pyridin-4-yl)-2-naphthamide Drug Info IC50 = 1260 nM [530812]
Dihydro-quinolinone Drug Info IC50 = 0.74 nM [530753]
SB-227931 Drug Info IC50 = 46 nM [527732]
SB-216995 Drug Info IC50 = 160 nM [530753]
Ro-3201195 Drug Info IC50 = 180 nM [529522]
4-(2-Ethyl-4-m-tolyl-thiazol-5-yl)-pyridine Drug Info IC50 = 15 nM [527737]
TYRPHOSTIN AG-1478 Drug Info IC50 = 560 nM [527230]
SB-218655 Drug Info IC50 = 25 nM [530753]
(5-amino-1-phenyl-1H-pyrazol-4-yl)phenylmethanone Drug Info IC50 = 570 nM [528056]
ML-3375 Drug Info IC50 = 1200 nM [526668]
PH-797804 Drug Info IC50 = 5 nM [528241]
BMS-582949 Drug Info IC50 = 3.5 nM [529348]
N-(3-(trifluoromethyl)benzyl)-4-phenoxybenzamide Drug Info IC50 = 450 nM [527747]
IN-1130 Drug Info IC50 = 4300 nM [529552]
ML-3163 Drug Info IC50 = 880 nM [526355]
N-(4-(trifluoromethyl)benzyl)-4-phenoxybenzamide Drug Info IC50 = 1400 nM [527747]
N-(3-(trifluoromethoxy)benzyl)-4-phenoxybenzamide Drug Info IC50 = 600 nM [527747]
SB-242235 Drug Info IC50 = 130 nM [529583]
ZM-336372 Drug Info IC50 = 180 nM [527229]
N-(4-methyl-benzyl)-4-phenoxy-benzamide Drug Info IC50 = 1600 nM [527747]
Dilmapimod Drug Info IC50 = 44 nM [552241]
PAMAPIMOD Drug Info IC50 = 14 nM [530550]
Talmapimod Drug Info IC50 = 9 nM [530550]
Action against Disease Model Losmapimod Inhibition of p38 mitogen-activated protein kinase improves nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia. Losmapimod improves nitric oxide-mediated vasodilatation in hypercholesterolemic patients, which is consistent with findings in previous translational animal models. These data support the hypothesis that attenuating the inflammatory milieu by inhibiting p38 MAPK activity improves NO activity, and p38 MAPK is a novel target for patients with cardiovascular disease. [553090] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations In isolated hearts from mice lacking the p38-MAPK activator, MAPK kinase 3 (MKK3), perfused at constant coronary pressure or flow, we measured the left ventricular developed pressure (LVDP) and the relationship between end-diastolic vol uMe and LVDP in the presence and absence of 10 ng/mL TNFalpha.Within 15 min at constant pressure, TNFalpha significantly reduced LVDP and coronary flow in outbred and mkk3(+/+) mice. This early negative inotropic effect was associated with a marked phosphorylation of both p38-MAPK and its indirect substrate, HSP27. In hearts lacking MKK3,TNFalpha failed to activate p38-MAPK or to cause significant contractile dysfunction. The actions of TNFalpha were similarly attenuated in MAPK-activated protein kinase 2 (MK2)-deficient hearts, which have a marked reduction in myocardial p38-MAPK protein content, and by the p38-MAPK catalytic site inhibitor SB203580 (1 micromol/l). Under conditions of constant coronary flow, the p38-MAPK activation and contractile depression induced by TNFalpha, though attenuated, remained sensitive to the absence of MKK3 or the presence of SB203580. The role of p38-MAPK in TNFalpha-induced contractile depression was confirmed in isolated murine cardiac myocytes exposed to SB203580 or lacking MKK3.T uMor necrosis factor activates p38-MAPK in the intact heart and in isolated cardiac myocytes through MKK3.This activation likely contributes to the early cardiodepressant action of TNFalpha. [526530]
References
Ref 526530Bioorg Med Chem Lett. 2003 Feb 10;13(3):347-50.Imidazopyrimidines, potent inhibitors of p38 MAP kinase.
Ref 529552Bioorg Med Chem Lett. 2008 Jul 15;18(14):4006-10. Epub 2008 Jun 6.Synthesis and biological evaluation of trisubstituted imidazole derivatives as inhibitors of p38alpha mitogen-activated protein kinase.
Ref 527722Bioorg Med Chem Lett. 2005 Nov 15;15(22):5095-9.Design and synthesis of 6-anilinoindazoles as selective inhibitors of c-Jun N-terminal kinase-3.
Ref 528429J Med Chem. 2006 Sep 21;49(19):5671-86.Discovery of aminoquinazolines as potent, orally bioavailable inhibitors of Lck: synthesis, SAR, and in vivo anti-inflammatory activity.
Ref 526668J Med Chem. 2003 Jul 17;46(15):3230-44.Novel substituted pyridinyl imidazoles as potent anticytokine agents with low activity against hepatic cytochrome P450 enzymes.
Ref 528108J Med Chem. 2006 Apr 6;49(7):2210-21.Discovery of 4-{4-[3-(pyridin-2-yl)-1H-pyrazol-4-yl]pyridin-2-yl}-N-(tetrahydro-2H- pyran-4-yl)benzamide (GW788388): a potent, selective, and orally active transforming growth factor-beta type I receptor inhibitor.
Ref 530497Bioorg Med Chem Lett. 2009 Dec 15;19(24):6872-6. Epub 2009 Oct 23.Structure-activity relationships of 6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7-ones: toward selective Abl inhibitors.
Ref 530497Bioorg Med Chem Lett. 2009 Dec 15;19(24):6872-6. Epub 2009 Oct 23.Structure-activity relationships of 6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7-ones: toward selective Abl inhibitors.
Ref 530812Bioorg Med Chem Lett. 2010 Apr 15;20(8):2560-3. Epub 2010 Mar 2.Amide-based inhibitors of p38alpha MAP kinase. Part 2: design, synthesis and SAR of potent N-pyrimidyl amides.
Ref 530753Bioorg Med Chem. 2010 Mar 15;18(6):2204-18. Epub 2010 Feb 8.In silico search for multi-target anti-inflammatories in Chinese herbs and formulas.
Ref 527732Bioorg Med Chem Lett. 2005 Nov 1;15(21):4666-70.The neuroprotective action of JNK3 inhibitors based on the 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole scaffold.
Ref 530753Bioorg Med Chem. 2010 Mar 15;18(6):2204-18. Epub 2010 Feb 8.In silico search for multi-target anti-inflammatories in Chinese herbs and formulas.
Ref 529522Bioorg Med Chem Lett. 2008 Jul 1;18(13):3745-8. Epub 2008 May 16.Microwave-assisted synthesis of 5-aminopyrazol-4-yl ketones and the p38(MAPK) inhibitor RO3201195 for study in Werner syndrome cells.
Ref 527737J Med Chem. 2005 Sep 22;48(19):5966-79.Novel inhibitor of p38 MAP kinase as an anti-TNF-alpha drug: discovery of N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (TAK-715) as a potent and orally active anti-rheumatoid arthritis agent.
Ref 527230Bioorg Med Chem Lett. 2004 Nov 1;14(21):5389-94.Novel, potent and selective anilinoquinazoline and anilinopyrimidine inhibitors of p38 MAP kinase.
Ref 530753Bioorg Med Chem. 2010 Mar 15;18(6):2204-18. Epub 2010 Feb 8.In silico search for multi-target anti-inflammatories in Chinese herbs and formulas.
Ref 528056J Med Chem. 2006 Mar 9;49(5):1562-75.Discovery of S-[5-amino-1-(4-fluorophenyl)-1H-pyrazol-4-yl]-[3-(2,3-dihydroxypropoxy)phenyl]methanone (RO3201195), an orally bioavailable and highly selective inhibitor of p38 MAP kinase.
Ref 526668J Med Chem. 2003 Jul 17;46(15):3230-44.Novel substituted pyridinyl imidazoles as potent anticytokine agents with low activity against hepatic cytochrome P450 enzymes.
Ref 528241Bioorg Med Chem Lett. 2006 Aug 15;16(16):4339-44. Epub 2006 Jun 12.Structure-activity relationships of triazolopyridine oxazole p38 inhibitors: identification of candidates for clinical development.
Ref 529348Bioorg Med Chem Lett. 2008 Mar 15;18(6):1762-7. Epub 2008 Feb 16.The discovery of (R)-2-(sec-butylamino)-N-(2-methyl-5-(methylcarbamoyl)phenyl) thiazole-5-carboxamide (BMS-640994)-A potent and efficacious p38alpha MAP kinase inhibitor.
Ref 527747Bioorg Med Chem Lett. 2005 Dec 1;15(23):5274-9. Epub 2005 Sep 19.Two classes of p38alpha MAP kinase inhibitors having a common diphenylether core but exhibiting divergent binding modes.
Ref 553090Inhibition of p38 mitogen-activated protein kinase improves nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia. Circulation. 2011 Feb 8;123(5):515-23. doi: 10.1161/CIRCULATIONAHA.110.971986. Epub 2011 Jan 24.
Ref 529552Bioorg Med Chem Lett. 2008 Jul 15;18(14):4006-10. Epub 2008 Jun 6.Synthesis and biological evaluation of trisubstituted imidazole derivatives as inhibitors of p38alpha mitogen-activated protein kinase.
Ref 526355J Med Chem. 2002 Jun 20;45(13):2733-40.From imidazoles to pyrimidines: new inhibitors of cytokine release.
Ref 527747Bioorg Med Chem Lett. 2005 Dec 1;15(23):5274-9. Epub 2005 Sep 19.Two classes of p38alpha MAP kinase inhibitors having a common diphenylether core but exhibiting divergent binding modes.
Ref 527747Bioorg Med Chem Lett. 2005 Dec 1;15(23):5274-9. Epub 2005 Sep 19.Two classes of p38alpha MAP kinase inhibitors having a common diphenylether core but exhibiting divergent binding modes.
Ref 529583Bioorg Med Chem Lett. 2008 Aug 1;18(15):4433-7. Epub 2008 Jun 12.Biphenyl amide p38 kinase inhibitors 4: DFG-in and DFG-out binding modes.
Ref 527229Bioorg Med Chem Lett. 2004 Nov 1;14(21):5383-7.A novel series of p38 MAP kinase inhibitors for the potential treatment of rheumatoid arthritis.
Ref 527747Bioorg Med Chem Lett. 2005 Dec 1;15(23):5274-9. Epub 2005 Sep 19.Two classes of p38alpha MAP kinase inhibitors having a common diphenylether core but exhibiting divergent binding modes.
Ref 552241SB 239063, a second-generation p38 mitogen-activated protein kinase inhibitor, reduces brain injury and neurological deficits in cerebral focal ischemia. J Pharmacol Exp Ther. 2001 Feb;296(2):312-21.
Ref 530550J Med Chem. 2010 Mar 25;53(6):2345-53.Selective p38alpha inhibitors clinically evaluated for the treatment of chronic inflammatory disorders.
Ref 530550J Med Chem. 2010 Mar 25;53(6):2345-53.Selective p38alpha inhibitors clinically evaluated for the treatment of chronic inflammatory disorders.

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