Parallel strategies for the preparation and selection of liver-targeted glucocorticoid receptor antagonists

Bioorg Med Chem Lett. 2007 Jan 1;17(1):40-4. doi: 10.1016/j.bmcl.2006.10.001. Epub 2006 Oct 5.

Abstract

Libraries of mifepristone analogs, MP-Acids, were designed and synthesized to increase the chances of identifying GR antagonists that possess liver-selective pharmacological profiles. MP-Acids were uniformly potent GR antagonists in binding and in cell-based functional assays. A high throughput pharmacokinetic selection strategy that employs the cassette dosing of MP-Acids was developed to identify liver-targeting compounds. Thus, resource-intensive in vivo assays to measure liver-selective pharmacology were enriched with GR antagonists that achieve high concentrations in the liver.

MeSH terms

  • Animals
  • Glucocorticoids / chemical synthesis
  • Glucocorticoids / chemistry*
  • Glucocorticoids / pharmacokinetics*
  • Liver / metabolism*
  • Mifepristone / analogs & derivatives*
  • Rats
  • Rats, Inbred Strains
  • Receptors, Glucocorticoid / antagonists & inhibitors*

Substances

  • Glucocorticoids
  • Receptors, Glucocorticoid
  • Mifepristone