Antidiabetic activity of passive nonsteroidal glucocorticoid receptor modulators.
Much has been learned about the consequences of glucocorticoid receptor antagonism by studying steroidal active antagonists such as RU-38486 (1). In the liver glucocorticoid receptor antagonism suppresses hepatic glucose production decreasing plasma glucose levels; however, extrahepatic antagonism produces several undesirable side effects including activation of the hypothalamic pituitary adrenal axis. A series of nonsteroidal passive N-(3-dibenzylamino-2-alkyl-phenyl)-methanesulfonamide glucocorticoid receptor modulators was discovered. Liver selective and systemically available members of this series were found and characterized in diabetes and side effect rodent models. A highly liver selective member of this series, acid 14, shows efficacy in the ob/ob model of diabetes. It lowers plasma glucose, cholesterol, and free fatty acid concentrations and reduces the rate of body weight gain. The structurally related systemically available passive modulator 12 lowers glucose, HbA(1c), triglyceride, free fatty acid, and cholesterol levels. Interestingly, it did not acutely activate the hypothalamic pituitary adrenal axis in unstressed CD-1 mice or have the abortive effects observed with 1. These results indicate that passive GR antagonists may have utility as antidiabetic agents.
Link
J T
JT
Metabolic Disease Research, Abbott Laboratories, 100 Abbott Park Road, Department 4CB, Room L-14, Building AP-10, Abbott Park, IL 60064-6098, USA. james.link@abbott.com
Sorensen
Bryan
B
Patel
Jyoti
J
Grynfarb
Marlena
M
Goos-Nilsson
Annika
A
Wang
Jiahong
J
Fung
Steven
S
Wilcox
Denise
D
Zinker
Brad
B
Nguyen
Phong
P
Hickman
Bach
B
Schmidt
James M
JM
Swanson
Sue
S
Tian
Zhenping
Z
Reisch
Thomas J
TJ
Rotert
Gary
G
Du
Jia
J
Lane
Benjamin
B
von Geldern
Thomas W
TW
Jacobson
Peer B
PB
D000469:Alkaline Phosphatase / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001596:Benzylamines / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D017930:Genes, Reporter; D005938:Glucocorticoids / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D008297:Male; D051379:Mice; D010913:Pituitary-Adrenal System / Q000187:drug effects; D011247:Pregnancy; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000235:genetics; D013449:Sulfonamides / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D014444:Tyrosine Transaminase / Q000096:biosynthesis; D014599:Uterus / Q000187:drug effects
C503903:(4-(4-((benzyl(2-methyl-3-((methylsulfonyl)amino)phenyl)amino)methyl)phenoxy)phenoxy)acetic acid; C503902:(5-(4-(((2,4-difluorobenzyl)(2-methyl-3-((methylsulfonyl)amino)phenyl)amino)methyl)phenoxy)-2-fluorophenoxy)acetic acid; D001596:Benzylamines; D005938:Glucocorticoids; D007004:Hypoglycemic Agents; D011965:Receptors, Glucocorticoid; D013449:Sulfonamides; D003907:Dexamethasone; D014444:Tyrosine Transaminase; D000469:Alkaline Phosphatase