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

J T Link; Bryan K Sorensen; Chunqiu Lai; Jiahong Wang; Steven Fung; Daisy Deng; Maurice Emery; Sherry Carroll; Marlena Grynfarb; Annika Goos-Nilsson; Thomas Von Geldern

doi:10.1016/j.bmcl.2004.06.021

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.

Authors

J T Link¹, Bryan K Sorensen, Chunqiu Lai, Jiahong Wang, Steven Fung, Daisy Deng, Maurice Emery, Sherry Carroll, Marlena Grynfarb, Annika Goos-Nilsson, Thomas Von Geldern

Affiliation

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.

MeSH terms

Half-Life
Hepatocytes / drug effects
Hepatocytes / metabolism
Hydroxymethylglutaryl-CoA Reductase Inhibitors / chemical synthesis*
Hydroxymethylglutaryl-CoA Reductase Inhibitors / chemistry
Hydroxymethylglutaryl-CoA Reductase Inhibitors / metabolism
Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacokinetics*
Receptors, Glucocorticoid / antagonists & inhibitors
Receptors, Glucocorticoid / chemistry
Receptors, Glucocorticoid / drug effects*

Substances

Hydroxymethylglutaryl-CoA Reductase Inhibitors
Receptors, Glucocorticoid