- Discovery of potent, selective sulfonylfuran urea endothelial lipase inhibitors.
Discovery of potent, selective sulfonylfuran urea endothelial lipase inhibitors.
Bioorganic & medicinal chemistry letters (2008-12-09)
Krista B Goodman, Michael J Bury, Mui Cheung, Maria A Cichy-Knight, Sarah E Dowdell, Allison K Dunn, Dennis Lee, Jeffrey A Lieby, Michael L Moore, Daryl A Scherzer, Deyou Sha, Dominic P Suarez, Dennis J Murphy, Mark R Harpel, Eric S Manas, Dean E McNulty, Roland S Annan, Rosalie E Matico, Benjamin K Schwartz, John J Trill, Thomas D Sweitzer, Da-Yuan Wang, Paul M Keller, John A Krawiec, Michael C Jaye
PMID19058966
摘要
Endothelial lipase (EL) activity has been implicated in HDL catabolism, vascular inflammation, and atherogenesis, and inhibitors are therefore expected to be useful for the treatment of cardiovascular disease. Sulfonylfuran urea 1 was identified in a high-throughput screening campaign as a potent and non-selective EL inhibitor. A lead optimization effort was undertaken to improve potency and selectivity, and modifications leading to improved LPL selectivity were identified. Radiolabeling studies were undertaken to establish the mechanism of action for these inhibitors, which were ultimately demonstrated to be irreversible inhibitors.
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