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 526530 | Bioorg Med Chem Lett. 2003 Feb 10;13(3):347-50.Imidazopyrimidines, potent inhibitors of p38 MAP kinase. | ||||
Ref 529552 | Bioorg 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 527722 | Bioorg 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 528429 | J 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 526668 | J 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 528108 | J 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 530497 | Bioorg 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 530497 | Bioorg 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 530812 | Bioorg 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 530753 | Bioorg 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 527732 | Bioorg 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 530753 | Bioorg 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 529522 | Bioorg 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 527737 | J 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 527230 | Bioorg Med Chem Lett. 2004 Nov 1;14(21):5389-94.Novel, potent and selective anilinoquinazoline and anilinopyrimidine inhibitors of p38 MAP kinase. | ||||
Ref 530753 | Bioorg 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 528056 | J 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 526668 | J 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 528241 | Bioorg 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 529348 | Bioorg 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 527747 | Bioorg 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 553090 | Inhibition 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 529552 | Bioorg 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 526355 | J Med Chem. 2002 Jun 20;45(13):2733-40.From imidazoles to pyrimidines: new inhibitors of cytokine release. | ||||
Ref 527747 | Bioorg 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 527747 | Bioorg 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 529583 | Bioorg 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 527229 | Bioorg 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 527747 | Bioorg 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 552241 | SB 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 530550 | J Med Chem. 2010 Mar 25;53(6):2345-53.Selective p38alpha inhibitors clinically evaluated for the treatment of chronic inflammatory disorders. | ||||
Ref 530550 | J 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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