Liver-Selective Glucocorticoid Antagonists:  A Novel Treatment for Type 2 Diabetes

• Published in: Journal of medicinal chemistry Vol. 47; no. 17; pp. 4213 - 4230
• Main Authors: von Geldern, Thomas W, Tu, Noah, Kym, Philip R, Link, James T, Jae, Hwan-Soo, Lai, Chunqiu, Apelqvist, Theresa, Rhonnstad, Patrik, Hagberg, Lars, Koehler, Konrad, Grynfarb, Marlena, Goos-Nilsson, Annika, Sandberg, Johnny, Österlund, Marie, Barkhem, Tomas, Höglund, Marie, Wang, Jiahong, Fung, Steven, Wilcox, Denise, Nguyen, Phong, Jakob, Clarissa, Hutchins, Charles, Färnegårdh, Mathias, Kauppi, Björn, Öhman, Lars, Jacobson, Peer B
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.08.2004; Amer Chemical Soc
• Subjects: Animals; Bile Acids and Salts - chemistry; Binding Sites; Biological and medical sciences; Bridged-Ring Compounds - chemical synthesis; Bridged-Ring Compounds - chemistry; Bridged-Ring Compounds - pharmacology; Cells, Cultured; Chemistry, Medicinal; CHO Cells; Computer Simulation; Cricetinae; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; General and cellular metabolism. Vitamins; Glucose - biosynthesis; Humans; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Hypothalamo-Hypophyseal System - drug effects; Hypothalamo-Hypophyseal System - physiology; Life Sciences & Biomedicine; Liver - metabolism; Male; Medical sciences; Mice; Models, Molecular; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pituitary-Adrenal System - drug effects; Pituitary-Adrenal System - physiology; Rats; Rats, Sprague-Dawley; Receptors, Glucocorticoid - antagonists & inhibitors; Receptors, Glucocorticoid - metabolism; Science & Technology; Structure-Activity Relationship; GLUCOSE; DISEASE; RATS; LONG-TERM TREATMENT; BILE-ACIDS; CORTISOL; DELIVERY; Type 2 diabetes; Endocrinopathy; Steroid; Corticosteroid; Acetylenic compound; Liver; Aniline derivatives; Selectivity; In vitro; Biological activity; In vivo; Hypoglycemic agent; Experimental disease; Treatment; Bile acid; Animal; Glucocorticoid receptor; Antagonist; Conjugated compound; Chemical synthesis; Aromatic amine
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0400045

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.