Liver-selective glucocorticoid antagonists: a novel treatment for type 2 diabetes.

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von Geldern TW, Tu N, Kym PR, Link JT, Jae HS, Lai C, Apelqvist T, Rhonnstad P, Hagberg L, Koehler K, Grynfarb M, Goos-Nilsson A, Sandberg J, Osterlund M, Barkhem T, Hoglund M, Wang J, Fung S, Wilcox D, Nguyen P, Jakob C, Hutchins C, Farnegardh M, Kauppi B, Ohman L, Jacobson PB

Liver-selective glucocorticoid antagonists: a novel treatment for type 2 diabetes.

J Med Chem. 2004 Aug 12;47(17):4213-30.

PubMed ID
15293993 [ View in PubMed
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Abstract

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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
MifepristoneGlucocorticoid receptorKi (nM)120N/AN/ADetails
MifepristoneGlucocorticoid receptorKi (nM)0.44N/AN/ADetails
MifepristoneGlucocorticoid receptorKi (nM)0.1N/AN/ADetails
MifepristoneProgesterone receptorKi (nM)0.64N/AN/ADetails