title: Selective glucocorticoid receptor nonsteroidal ligands completely antagonize the dexamethasone mediated induction of enzymes involved in gluconeogenesis and glutamine metabolism.
abstract: Glucocorticoids (GCs) are vital multi-faceted hormones with recognized effects on carbohydrate, protein and lipid metabolism. Previous studies with the steroid antagonist, RU486 have underscored the essential role of GCs in the regulation of these metabolic pathways. This article describes the discovery and characterization of novel GRalpha selective nonsteroidal antagonists (NSGCAs). NSGCAs 2 and 3 are spirocyclic dihydropyridine derivatives that selectively bind the GRalpha with IC(50s) of 2 and 1.5 nM, respectively. Importantly, these compounds are full antagonists of the induction by dexamethasone (Dex) of marker genes for glucose and glutamine metabolism; the tyrosine amino transferase (TAT) and glutamine synthetase (GS) enzymes, respectively. In contrast, GC-dependent transcriptional repression of the collagenase 1 (MMP-1) enzyme, an established GRalpha responsive proinflammatory gene; is poorly antagonized by these compounds. These NSGCAs might have useful applications as tools in metabolic research and drug discovery.
authors.affiliation: Department of Metabolic Disorders, Merck Research Laboratories, P.O. Box 2000, Mail Code: RY80N-C31, Rahway, NJ 07065, USA. monica_einstein@merck.com
authors.forename: Monica
authors.initials: M
authors.lastname: Einstein
authors.forename: Mark
authors.initials: M
authors.lastname: Greenlee
authors.forename: Greg
authors.initials: G
authors.lastname: Rouen
authors.forename: Ayesha
authors.initials: A
authors.lastname: Sitlani
authors.forename: Joe
authors.initials: J
authors.lastname: Santoro
authors.forename: Chuanlin
authors.initials: C
authors.lastname: Wang
authors.forename: Shilpa
authors.initials: S
authors.lastname: Pandit
authors.forename: Paul
authors.initials: P
authors.lastname: Mazur
authors.forename: Isabella
authors.initials: I
authors.lastname: Smalera
authors.forename: Alehna Pm
authors.initials: AP
authors.lastname: Weaver
authors.forename: Ying Ying
authors.initials: YY
authors.lastname: Zeng
authors.forename: Lan
authors.initials: L
authors.lastname: Ge
authors.forename: Theresa
authors.initials: T
authors.lastname: Kelly
authors.forename: Tony
authors.initials: T
authors.lastname: Paiva
authors.forename: Wayne
authors.initials: W
authors.lastname: Geissler
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Mosley
authors.forename: Joanne
authors.initials: J
authors.lastname: Williamson
authors.forename: Amjad
authors.initials: A
authors.lastname: Ali
authors.forename: Jim
authors.initials: J
authors.lastname: Balkovec
authors.forename: Georgianna
authors.initials: G
authors.lastname: Harris
mesh_terms: D000818:Animals; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology*; D005938:Glucocorticoids / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects*; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000201:enzymology; D020128:Inhibitory Concentration 50; D008024:Ligands; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D015394:Molecular Structure; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D005938:Glucocorticoids; D008024:Ligands; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; D005973:Glutamine; D003907:Dexamethasone; D020781:Matrix Metalloproteinase 1