Target Validation Information
TTD ID T65864
Target Name Stress-activated protein kinase 2a (p38 alpha)
Type of Target
Clinical trial
Drug Potency against Target Dilmapimod Drug Info IC50 = 44 nM [22]
(5-amino-1-phenyl-1H-pyrazol-4-yl)phenylmethanone Drug Info IC50 = 570 nM [10]
4-(2-Ethyl-4-m-tolyl-thiazol-5-yl)-pyridine Drug Info IC50 = 15 nM [8]
6-o-tolylquinazolin-2-amine Drug Info IC50 = 3903 nM [13]
BMS-582949 Drug Info IC50 = 3.5 nM [14]
Dihydro-quinolinone Drug Info IC50 = 0.74 nM [20]
GW-788388 Drug Info IC50 = 7280 nM [11]
IN-1130 Drug Info IC50 = 4300 nM [16]
IN-1166 Drug Info IC50 = 1030 nM [16]
ML-3163 Drug Info IC50 = 880 nM [1]
ML-3375 Drug Info IC50 = 1200 nM [3]
ML-3403 Drug Info IC50 = 990 nM [3]
N-(3-(trifluoromethoxy)benzyl)-4-phenoxybenzamide Drug Info IC50 = 600 nM [9]
N-(3-(trifluoromethyl)benzyl)-4-phenoxybenzamide Drug Info IC50 = 450 nM [9]
N-(4-(trifluoromethyl)benzyl)-4-phenoxybenzamide Drug Info IC50 = 1400 nM [9]
N-(4-fluorobenzyl)-N-(pyridin-4-yl)-2-naphthamide Drug Info IC50 = 1260 nM [21]
N-(4-methyl-benzyl)-4-phenoxy-benzamide Drug Info IC50 = 1600 nM [9]
PAMAPIMOD Drug Info IC50 = 14 nM [19]
PD-0166326 Drug Info IC50 = 140 nM [18]
PD-0173956 Drug Info IC50 = 50 nM [18]
PH-797804 Drug Info IC50 = 5 nM [12]
Phenyl-(3-phenyl-1H-indazol-6-yl)-amine Drug Info IC50 = 30 nM [6]
Ro-3201195 Drug Info IC50 = 180 nM [15]
RWJ-68354 Drug Info IC50 = 1500 nM [2]
SB-216995 Drug Info IC50 = 160 nM [20]
SB-218655 Drug Info IC50 = 25 nM [20]
SB-227931 Drug Info IC50 = 46 nM [7]
SB-242235 Drug Info IC50 = 130 nM [17]
Talmapimod Drug Info IC50 = 9 nM [19]
Tyrphostin ag-1478 Drug Info IC50 = 560 nM [5]
ZM-336372 Drug Info IC50 = 180 nM [4]
Action against Disease Model Losmapimod Drug Info 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. [23]
References
REF 1 From imidazoles to pyrimidines: new inhibitors of cytokine release. J Med Chem. 2002 Jun 20;45(13):2733-40.
REF 2 Imidazopyrimidines, potent inhibitors of p38 MAP kinase. Bioorg Med Chem Lett. 2003 Feb 10;13(3):347-50.
REF 3 Novel substituted pyridinyl imidazoles as potent anticytokine agents with low activity against hepatic cytochrome P450 enzymes. J Med Chem. 2003 Jul 17;46(15):3230-44.
REF 4 A novel series of p38 MAP kinase inhibitors for the potential treatment of rheumatoid arthritis. Bioorg Med Chem Lett. 2004 Nov 1;14(21):5383-7.
REF 5 Novel, potent and selective anilinoquinazoline and anilinopyrimidine inhibitors of p38 MAP kinase. Bioorg Med Chem Lett. 2004 Nov 1;14(21):5389-94.
REF 6 Design and synthesis of 6-anilinoindazoles as selective inhibitors of c-Jun N-terminal kinase-3. Bioorg Med Chem Lett. 2005 Nov 15;15(22):5095-9.
REF 7 The neuroprotective action of JNK3 inhibitors based on the 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole scaffold. Bioorg Med Chem Lett. 2005 Nov 1;15(21):4666-70.
REF 8 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 (T... J Med Chem. 2005 Sep 22;48(19):5966-79.
REF 9 Two classes of p38alpha MAP kinase inhibitors having a common diphenylether core but exhibiting divergent binding modes. Bioorg Med Chem Lett. 2005 Dec 1;15(23):5274-9.
REF 10 Discovery of S-[5-amino-1-(4-fluorophenyl)-1H-pyrazol-4-yl]-[3-(2,3-dihydroxypropoxy)phenyl]methanone (RO3201195), an orally bioavailable and highl... J Med Chem. 2006 Mar 9;49(5):1562-75.
REF 11 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 orall... J Med Chem. 2006 Apr 6;49(7):2210-21.
REF 12 Structure-activity relationships of triazolopyridine oxazole p38 inhibitors: identification of candidates for clinical development. Bioorg Med Chem Lett. 2006 Aug 15;16(16):4339-44.
REF 13 Discovery of aminoquinazolines as potent, orally bioavailable inhibitors of Lck: synthesis, SAR, and in vivo anti-inflammatory activity. J Med Chem. 2006 Sep 21;49(19):5671-86.
REF 14 The discovery of (R)-2-(sec-butylamino)-N-(2-methyl-5-(methylcarbamoyl)phenyl) thiazole-5-carboxamide (BMS-640994)-A potent and efficacious p38alph... Bioorg Med Chem Lett. 2008 Mar 15;18(6):1762-7.
REF 15 Microwave-assisted synthesis of 5-aminopyrazol-4-yl ketones and the p38(MAPK) inhibitor RO3201195 for study in Werner syndrome cells. Bioorg Med Chem Lett. 2008 Jul 1;18(13):3745-8.
REF 16 Synthesis and biological evaluation of trisubstituted imidazole derivatives as inhibitors of p38alpha mitogen-activated protein kinase. Bioorg Med Chem Lett. 2008 Jul 15;18(14):4006-10.
REF 17 Biphenyl amide p38 kinase inhibitors 4: DFG-in and DFG-out binding modes. Bioorg Med Chem Lett. 2008 Aug 1;18(15):4433-7.
REF 18 Structure-activity relationships of 6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7-ones: toward selective Abl inhibitors. Bioorg Med Chem Lett. 2009 Dec 15;19(24):6872-6.
REF 19 Selective p38alpha inhibitors clinically evaluated for the treatment of chronic inflammatory disorders. J Med Chem. 2010 Mar 25;53(6):2345-53.
REF 20 In silico search for multi-target anti-inflammatories in Chinese herbs and formulas. Bioorg Med Chem. 2010 Mar 15;18(6):2204-2218.
REF 21 Amide-based inhibitors of p38alpha MAP kinase. Part 2: design, synthesis and SAR of potent N-pyrimidyl amides. Bioorg Med Chem Lett. 2010 Apr 15;20(8):2560-3.
REF 22 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 23 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.

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