Synthesis, activity, metabolic stability, and pharmacokinetics of glucocorticoid receptor modulator-statin hybrids.
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.
Link
J T
JT
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
Sorensen
Bryan K
BK
Lai
Chunqiu
C
Wang
Jiahong
J
Fung
Steven
S
Deng
Daisy
D
Emery
Maurice
M
Carroll
Sherry
S
Grynfarb
Marlena
M
Goos-Nilsson
Annika
A
Von Geldern
Thomas
T
D006207:Half-Life; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000187:drug effects*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011965:Receptors, Glucocorticoid