Liver-selective glucocorticoid antagonists: a novel treatment for type 2 diabetes.
Hepatic blockade of glucocorticoid receptors (GR) suppresses glucose production and thus decreases circulating glucose levels, but systemic glucocorticoid antagonism can produce adrenal insufficiency and other undesirable side effects. These hepatic and systemic responses might be dissected, leading to liver-selective pharmacology, when a GR antagonist is linked to a bile acid in an appropriate manner. Bile acid conjugation can be accomplished with a minimal loss of binding affinity for GR. The resultant conjugates remain potent in cell-based functional assays. A novel in vivo assay has been developed to simultaneously evaluate both hepatic and systemic GR blockade; this assay has been used to optimize the nature and site of the linker functionality, as well as the choice of the GR antagonist and the bile acid. This optimization led to the identification of A-348441, which reduces glucose levels and improves lipid profiles in an animal model of diabetes.
von Geldern
Thomas W
TW
Metabolic Disease Research and Structural Biology Departments, Global Pharmaceutical Discovery, Abbott Laboratories, Abbott Park, Illinois 60064, UDA. thomas.vongeldern@abbott.com
Tu
Noah
N
Kym
Philip R
PR
Link
James T
JT
Jae
Hwan-Soo
HS
Lai
Chunqiu
C
Apelqvist
Theresa
T
Rhonnstad
Patrik
P
Hagberg
Lars
L
Koehler
Konrad
K
Grynfarb
Marlena
M
Goos-Nilsson
Annika
A
Sandberg
Johnny
J
Osterlund
Marie
M
Barkhem
Tomas
T
Höglund
Marie
M
Wang
Jiahong
J
Fung
Steven
S
Wilcox
Denise
D
Nguyen
Phong
P
Jakob
Clarissa
C
Hutchins
Charles
C
Färnegårdh
Mathias
M
Kauppi
Björn
B
Ohman
Lars
L
Jacobson
Peer B
PB
D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry; D001665:Binding Sites; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D002478:Cells, Cultured; D003198:Computer Simulation; D006224:Cricetinae; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D005947:Glucose / Q000096:biosynthesis; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D001647:Bile Acids and Salts; D001952:Bridged-Ring Compounds; D007004:Hypoglycemic Agents; D011965:Receptors, Glucocorticoid; D005947:Glucose