Target Validation Information
Target ID T69912
Target Name Lipoprotein-associated phospholipase A2
Target Type
Clinical Trial
Drug Potency against Target (E)-(thiophen-2-ylmethylidene)amino benzoate Drug Info IC50 = 11200 nM [527433]
Darapladib Drug Info IC50 = 0.27 nM [553006]
4-fluorobenzaldehyde O-benzoyloxime Drug Info IC50 = 4400 nM [528384]
Benzaldehyde O-benzoyloxime Drug Info IC50 = 3800 nM [528384]
3,4-difluorobenzaldehyde O-benzoyloxime Drug Info IC50 = 2000 nM [528384]
Action against Disease Model Darapladib Preclinical studies in diabetic-hypercholesterolemic swine (useful for the study of h uMan atherosclerosis mechanisms) demonstrated that darapladib attenuated the progression ofarterial plaques to a higher-risk phenotype by reducing the n uMber of inflammatory macrophages within plaques and dampening T-cell responses. [552985] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations Transgenic mice overexpressing h uMan PAF-AH II in neurons were generated and enzyme expressions were examined biochemically and histochemically. The mice were subjected to 60 minutes of transient middle cerebral artery occlusion followed by reperfusion for 24 hours. The infarction and apoptosis were estimated by TTC staining and fluorescence TUNEL staining, respectively.Overexpression of PAF-AH II was found in brains of transgenic mice by Western blot and enzymatic activity analyses. In immunohistochemistry, h uMan PAF-AH II expression was found throughout the central nervous system, especially in neurons of neocortex, hippocampus, and basal ganglia. The neurological deficit scores, cerebral edema index, and relative infarction vol uMe were all significantly (P<0.05) lower in transgenic mice (1.30+/-0.72, 1.12+/-0.04, and 14.0+/-7.7%, respectively) than in wild-type mice (2.56+/-0.93, 1.23+/-0.12, and 31.9+/-9.7%, respectively). Percentages of apoptotic cells were also significantly (P<0.001) lower in transgenic mice (cortex, 5.2+/-3.3%; hippocampus, 3.4+/-7.0%) than in wild-type mice (cortex, 41.1+/-16.9%; hippocampus, 58.9+/-15.3%).These results indicate that PAF-AH II exerts strong neuroprotective effects against ischemic injury and suggest a possibility for clinical use of this enzyme in cerebral ischemia. [552985]
References
Ref 552985Darapladib, a reversible lipoprotein-associated phospholipase A2 inhibitor, for the oral treatment of atherosclerosis and coronary artery disease. IDrugs. 2009 Oct;12(10):648-55.
Ref 527433Bioorg Med Chem Lett. 2005 Mar 1;15(5):1525-7.(E)-Phenyl- and -heteroaryl-substituted O-benzoyl-(or acyl)oximes as lipoprotein-associated phospholipase A2 inhibitors.
Ref 553006Darapladib. Expert Opin Investig Drugs. 2010 Jan;19(1):161-8. doi: 10.1517/13543780903501513.
Ref 528384Bioorg Med Chem Lett. 2006 Nov 1;16(21):5576-9. Epub 2006 Aug 21.Potent inhibitors of lipoprotein-associated phospholipase A(2): benzaldehyde O-heterocycle-4-carbonyloxime.
Ref 528384Bioorg Med Chem Lett. 2006 Nov 1;16(21):5576-9. Epub 2006 Aug 21.Potent inhibitors of lipoprotein-associated phospholipase A(2): benzaldehyde O-heterocycle-4-carbonyloxime.
Ref 528384Bioorg Med Chem Lett. 2006 Nov 1;16(21):5576-9. Epub 2006 Aug 21.Potent inhibitors of lipoprotein-associated phospholipase A(2): benzaldehyde O-heterocycle-4-carbonyloxime.

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