Synthesis, activity, metabolic stability, and pharmacokinetics of glucocorticoid receptor modulator-statin hybrids |
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Authors: | Link J T Sorensen Bryan K Lai Chunqiu Wang Jiahong Fung Steven Deng Daisy Emery Maurice Carroll Sherry Grynfarb Marlena Goos-Nilsson Annika Von Geldern Thomas |
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Affiliation: | Metabolic Disease Research, Abbott Laboratories, Dept 4 CB, Bldg. AP-10, Rm. L-14, 100 Abbott Park Road, Abbott Park, IL 60064-6098, USA. james.link@abbott.com |
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Abstract: | The synthesis, activity, metabolic stability, and pharmacokinetics of steroidal and nonsteroidal glucocorticoid receptor modulator-statin hybrids is reported. Potent steroidal antagonist-statin hybrids like 22 (h-GR binding IC(50)=7 nM) and nonsteroidal modulator hybrids like 16 (h-GR binding IC(50)=2 nM) were discovered. Appending a 'statin'-like diol-acid group to the modulators dramatically improved metabolic stability (and in some cases hepatocyte activity), but did not impart hepatoselectivity. |
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