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
DrugTargetPropertyMeasurementpHTemperature (°C)
CelecoxibProstaglandin G/H synthase 2IC 50 (nM)40N/AN/ADetails
CelecoxibProstaglandin G/H synthase 2IC 50 (nM)54N/AN/ADetails
IndomethacinProstaglandin G/H synthase 1IC 50 (nM)50N/AN/ADetails
IndomethacinProstaglandin G/H synthase 2IC 50 (nM)750N/AN/ADetails
RofecoxibProstaglandin G/H synthase 1IC 50 (nM)26000N/AN/ADetails
RofecoxibProstaglandin G/H synthase 2IC 50 (nM)340N/AN/ADetails