Synthesis, activity, metabolic stability, and pharmacokinetics of glucocorticoid receptor modulator–statin hybrids

The synthesis and hepatic selectivity of steroidal and nonsteroidal glucocorticoid receptor modulator–statin hybrids (e.g., 16 h-GR binding IC 50=2 nm) is reported. 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.