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

  • Bioorg Med Chem Lett. 2004 Aug 16;14(16):4173-8. doi: 10.1016/j.bmcl.2004.06.021.
J T Link  1 ,  Bryan K Sorensen ,  Chunqiu Lai ,  Jiahong Wang ,  Steven Fung ,  Daisy Deng ,  Maurice Emery ,  Sherry Carroll ,  Marlena Grynfarb ,  Annika Goos-Nilsson ,  Thomas Von Geldern
Affiliations
  • 1. Metabolic Disease Research, Abbott Laboratories, Dept 4 CB, Bldg. AP-10, Rm. L-14, 100 Abbott Park Road, Abbott Park, IL 60064-6098, USA. [email protected]
PMID: 15261265 DOI: 10.1016/j.bmcl.2004.06.021
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.