Indole Inhibitors of Human Nonpancreatic Secretory Phospholipase A2. 3. Indole-3-glyoxamides
| Autor: | Robert D. Dillard, Susan E. Draheim, Bach Nicholas J, Cynthia D. Sommers, Amy C. Smith, Emma R. McKinney, Noel D. Jones, Jennifer L. Olkowski, Edward David Mihelich, Jean-Pierre Wery, David W. Snyder, Lawrence W. Hartley, Donald G. Carlson, Richard Walter Schevitz, Nickolay Y. Chirgadze, Dennis R. Berry, David K. Clawson, Lea M. Johnson |
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| Rok vydání: | 1996 |
| Předmět: |
chemistry.chemical_classification
Indole test Magnetic Resonance Spectroscopy biology Biological activity Phospholipase Crystallography X-Ray Chemical synthesis Mass Spectrometry Phospholipases A Phospholipases A2 Structure-Activity Relationship chemistry.chemical_compound Sulfonylurea Compounds Enzyme Phospholipase A2 Biochemistry chemistry Biosynthesis Enzyme inhibitor Drug Discovery biology.protein Humans Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 39:5159-5175 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Phospholipases (PLAs) produce rate-limiting precursors in the biosynthesis of various types of biologically active lipids involved in inflammatory processes. Increased levels of human nonpancreatic secretory phospholipase A2 (hnps-PLA2) have been detected in several pathological conditions. An inhibitor of this enzyme could have therapeutic utility. A broad screening program was carried out to identify chemical structures which could inhibit hnps-PLA2. One of the lead compounds generated by the screening program was 5-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid (13a). We describe the syntheses, structure−activity relationships, and pharmacological activities of a series of indole-3-acetamides and related compounds derived from this lead. This SAR was undertaken with the aid of X-ray crystal structures of complexes between the inhibitors and hnps-PLA2 which were of great value in directing the SAR. |
| Databáze: | OpenAIRE |
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