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.
Metabolic Disease Research and Structural Biology Departments, Global Pharmaceutical Discovery, Abbott Laboratories, Abbott Park, Illinois 60064, UDA. thomas.vongeldern@abbott.com
Thomas W
TW
von Geldern
Noah
N
Tu
Philip R
PR
Kym
James T
JT
Link
Hwan-Soo
HS
Jae
Chunqiu
C
Lai
Theresa
T
Apelqvist
Patrik
P
Rhonnstad
Lars
L
Hagberg
Konrad
K
Koehler
Marlena
M
Grynfarb
Annika
A
Goos-Nilsson
Johnny
J
Sandberg
Marie
M
Osterlund
Tomas
T
Barkhem
Marie
M
Höglund
Jiahong
J
Wang
Steven
S
Fung
Denise
D
Wilcox
Phong
P
Nguyen
Clarissa
C
Jakob
Charles
C
Hutchins
Mathias
M
Färnegårdh
Björn
B
Kauppi
Lars
L
Ohman
Peer B
PB
Jacobson
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