Discovery of Potent and Selective Inhibitors of Human Platelet-Type 12- Lipoxygenase
| Autor: | Michael Holinstat, David A. Taylor-Fishwick, David J. Maloney, J. Brian Jameson, Jerry L. Nadler, William Leister, Michelle Armstrong, Ganesha Rai, Theodore R. Holman, Netra Joshi, James M. Bougie, Ajit Jadhav, Lena Schultz, Steve Perry, Anton Simeonov, Victor Kenyon |
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| Rok vydání: | 2011 |
| Předmět: |
Blood Platelets
Stereochemistry Stereoisomerism Arachidonate 12-Lipoxygenase Article Islets of Langerhans Mice Structure-Activity Relationship Lipoxygenase Non-competitive inhibition Drug Discovery Animals Humans Structure–activity relationship 12-Hydroxy-5 8 10 14-eicosatetraenoic Acid Lipoxygenase Inhibitors chemistry.chemical_classification Sheep biology Chemistry Active site Small molecule Chiral column chromatography Kinetics Enzyme Biochemistry biology.protein Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 54:5485-5497 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | We report the discovery of novel small molecule inhibitors of platelet type 12-human lipoxygenase, which display nanomolar activity against the purified enzyme, using a quantitative high throughput screen (qHTS) on a library of 153,607 compounds. These compounds also exhibit excellent specificity, >50-fold selectivity vs. the paralogs, 5-human lipoxygenase, reticulocyte 15-human lipoxygenase type-1, and epithelial 15-human lipoxygenase type-2, and >100-fold selectivity vs. ovine cyclooxygenase-1 and human cyclooxygenase-2. Kinetic experiments indicate this chemotype is a non-competitive inhibitor that does not reduce the active site iron. Moreover, chiral HPLC separation of two of the racemic lead molecules revealed a strong preference for the (–)-enantiomers (IC50 of 0.43 +/- 0.04 and 0.38 +/- 0.05 μM) compared to the (+)-enantiomers (IC50 of >25 μM for both), indicating a fine degree of selectivity in the active site due to chiral geometry. In addition, these compounds demonstrate efficacy in cellular models, which underscores their relevance to disease modification. |
| Databáze: | OpenAIRE |
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