Cyclooxygenase-1-selective inhibitors based on the (E)-2'-des-methyl-sulindac sulfide scaffold.
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Liedtke AJ, Crews BC, Daniel CM, Blobaum AL, Kingsley PJ, Ghebreselasie K, Marnett LJ
Cyclooxygenase-1-selective inhibitors based on the (E)-2'-des-methyl-sulindac sulfide scaffold.
J Med Chem. 2012 Mar 8;55(5):2287-300. doi: 10.1021/jm201528b. Epub 2012 Feb 14.
- PubMed ID
- 22263894 [ View in PubMed]
- Abstract
Prostaglandins (PGs) are powerful lipid mediators in many physiological and pathophysiological responses. They are produced by oxidation of arachidonic acid (AA) by cyclooxygenases (COX-1 and COX-2) followed by metabolism of endoperoxide intermediates by terminal PG synthases. PG biosynthesis is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). Specific inhibition of COX-2 has been extensively investigated, but relatively few COX-1-selective inhibitors have been described. Recent reports of a possible contribution of COX-1 in analgesia, neuroinflammation, or carcinogenesis suggest that COX-1 is a potential therapeutic target. We designed, synthesized, and evaluated a series of (E)-2'-des-methyl-sulindac sulfide (E-DMSS) analogues for inhibition of COX-1. Several potent and selective inhibitors were discovered, and the most promising compounds were active against COX-1 in intact ovarian carcinoma cells (OVCAR-3). The compounds inhibited tumor cell proliferation but only at concentrations >100-fold higher than the concentrations that inhibit COX-1 activity. E-DMSS analogues may be useful probes of COX-1 biology in vivo and promising leads for COX-1-targeted therapeutic agents.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Celecoxib Prostaglandin G/H synthase 2 IC 50 (nM) 40 N/A N/A Details Celecoxib Prostaglandin G/H synthase 2 IC 50 (nM) 54 N/A N/A Details Indomethacin Prostaglandin G/H synthase 1 IC 50 (nM) 50 N/A N/A Details Indomethacin Prostaglandin G/H synthase 2 IC 50 (nM) 750 N/A N/A Details Rofecoxib Prostaglandin G/H synthase 1 IC 50 (nM) 26000 N/A N/A Details Rofecoxib Prostaglandin G/H synthase 2 IC 50 (nM) 340 N/A N/A Details