title: Synthesis, activity, metabolic stability, and pharmacokinetics of glucocorticoid receptor modulator-statin hybrids.
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.
authors.affiliation: 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
authors.forename: J T
authors.initials: JT
authors.lastname: Link
authors.forename: Bryan K
authors.initials: BK
authors.lastname: Sorensen
authors.forename: Chunqiu
authors.initials: C
authors.lastname: Lai
authors.forename: Jiahong
authors.initials: J
authors.lastname: Wang
authors.forename: Steven
authors.initials: S
authors.lastname: Fung
authors.forename: Daisy
authors.initials: D
authors.lastname: Deng
authors.forename: Maurice
authors.initials: M
authors.lastname: Emery
authors.forename: Sherry
authors.initials: S
authors.lastname: Carroll
authors.forename: Marlena
authors.initials: M
authors.lastname: Grynfarb
authors.forename: Annika
authors.initials: A
authors.lastname: Goos-Nilsson
authors.forename: Thomas
authors.initials: T
authors.lastname: Von Geldern
mesh_terms: 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*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011965:Receptors, Glucocorticoid