دورية أكاديمية
Pharmacological characterization of 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (JNJ-42041935), a potent and selective hypoxia-inducible factor prolyl hydroxylase inhibitor.
| العنوان: | Pharmacological characterization of 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (JNJ-42041935), a potent and selective hypoxia-inducible factor prolyl hydroxylase inhibitor. |
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| المؤلفون: | Barrett TD; Cardiovascular Metabolic Research, Johnson and Johnson Pharmaceutical Research and Development LLC, 3210 Merryfield Row, San Diego, CA 92121, USA. tbarret1@its.jnj.com, Palomino HL, Brondstetter TI, Kanelakis KC, Wu X, Haug PV, Yan W, Young A, Hua H, Hart JC, Tran DT, Venkatesan H, Rosen MD, Peltier HM, Sepassi K, Rizzolio MC, Bembenek SD, Mirzadegan T, Rabinowitz MH, Shankley NP |
| المصدر: | Molecular pharmacology [Mol Pharmacol] 2011 Jun; Vol. 79 (6), pp. 910-20. Date of Electronic Publication: 2011 Mar 03. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0035623 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-0111 (Electronic) Linking ISSN: 0026895X NLM ISO Abbreviation: Mol Pharmacol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics |
| مواضيع طبية MeSH: | Benzimidazoles/*pharmacology , Enzyme Inhibitors/*pharmacology , Hypoxia-Inducible Factor 1, alpha Subunit/*antagonists & inhibitors , Procollagen-Proline Dioxygenase/*antagonists & inhibitors , Pyrazoles/*pharmacology, Amino Acid Sequence ; Animals ; Cell Line, Tumor ; Female ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Mice ; Molecular Sequence Data ; Procollagen-Proline Dioxygenase/chemistry ; Procollagen-Proline Dioxygenase/metabolism ; Protein Binding ; Rats ; Rats, Inbred Lew |
| مستخلص: | The hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) enzymes represent novel targets for the treatment of anemia, ulcerative colitis, and ischemic and metabolic disease inter alia. We have identified a novel small-molecule inhibitor of PHD, 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (JNJ-42041935), through structure-based drug design methods. The pharmacology of JNJ-42041935 was investigated in enzyme, cellular, and whole-animal systems and was compared with other compounds described in the literature as PHD inhibitors. JNJ-42041935, was a potent (pK(I) = 7.3-7.9), 2-oxoglutarate competitive, reversible, and selective inhibitor of PHD enzymes. In addition, JNJ-42041935 was used to compare the effect of selective inhibition of PHD to intermittent, high doses (50 μg/kg i.p.) of an exogenous erythropoietin receptor agonist in an inflammation-induced anemia model in rats. JNJ-42041935 (100 μmol/kg, once a day for 14 days) was effective in reversing inflammation-induced anemia, whereas erythropoietin had no effect. The results demonstrate that JNJ-42041935 is a new pharmacological tool, which can be used to investigate PHD inhibition and demonstrate that PHD inhibitors offer great promise for the treatment of inflammation-induced anemia. |
| المشرفين على المادة: | 0 (1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid) 0 (Benzimidazoles) 0 (Enzyme Inhibitors) 0 (Hif1a protein, mouse) 0 (Hif1a protein, rat) 0 (Hypoxia-Inducible Factor 1, alpha Subunit) 0 (Pyrazoles) EC 1.14.11.2 (Procollagen-Proline Dioxygenase) |
| تواريخ الأحداث: | Date Created: 20110305 Date Completed: 20110801 Latest Revision: 20110518 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1124/mol.110.070508 |
| PMID: | 21372172 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1521-0111 |
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| DOI: | 10.1124/mol.110.070508 |