Selective glucocorticoid receptor nonsteroidal ligands completely antagonize the dexamethasone mediated induction of enzymes involved in gluconeogenesis and glutamine metabolism.
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.
Einstein
Monica
M
Department of Metabolic Disorders, Merck Research Laboratories, P.O. Box 2000, Mail Code: RY80N-C31, Rahway, NJ 07065, USA. monica_einstein@merck.com
Greenlee
Mark
M
Rouen
Greg
G
Sitlani
Ayesha
A
Santoro
Joe
J
Wang
Chuanlin
C
Pandit
Shilpa
S
Mazur
Paul
P
Smalera
Isabella
I
Weaver
Alehna Pm
AP
Zeng
Ying Ying
YY
Ge
Lan
L
Kelly
Theresa
T
Paiva
Tony
T
Geissler
Wayne
W
Mosley
Ralph T
RT
Williamson
Joanne
J
Ali
Amjad
A
Balkovec
Jim
J
Harris
Georgianna
G
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
D005938:Glucocorticoids; D008024:Ligands; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; D005973:Glutamine; D003907:Dexamethasone; D020781:Matrix Metalloproteinase 1