An Evaluation of a C-Glucuronide as a liver targeting group: conjugate of a glucocorticoid antagonist

doi:10.1016/S0960-894X(03)00431-1

Bioorganic & Medicinal Chemistry Letters

Volume 13, Issue 14, 21 July 2003, Pages 2307-2310

https://doi.org/10.1016/S0960-894X(03)00431-1 Get rights and content

Abstract

A β-C-glucuronide conjugate of the glucocorticoid receptor antagonist, Mifepristone 1, was prepared which maintained binding affinity, had modest in vitro activity, and was metabolically more stable than the parent. Pharmacokinetic studies suggest that the conjugate is recognized by the liver like O-glucuronides and may undergo a portion of the enterohepatic recirculation loop.

The C-Glucuronide conjugate 14 was evaluated for its glucocorticoid receptor antagonist activity, metabolic stability, and ability to target the liver.

References (20)

J.E. Friedman et al.
J. Biol. Chem.
(1997)
S. Ichikawa et al.
J. Am. Chem. Soc.
(1999)
R. Kurukulasuriya et al.
Curr. Med. Chem.
(2003)
C.H. Bamberger et al.
Endocrine Rev.
(1996)
N. Kraus-Friedman
Physiol. Rev.
(1984)
D. Argaud et al.
Diabetes
(1996)
M. Truss et al.
Endocrine Rev.
(1993)
M.J. Coughlan et al.
Ann. Reports Med. Chem.
(2002)
L. Laue et al.
J. Clin. Endocrinol. Metab.
(1990)
X. Bertagna et al.
J. Clin. Endocrinol. Metab.
(1994)

There are more references available in the full text version of this article.

Cited by (14)

Discovery of liver selective non-steroidal glucocorticoid receptor antagonist as novel antidiabetic agents
2012, Bioorganic and Medicinal Chemistry Letters
Series of benzyl-phenoxybenzyl amino-phenyl acid derivatives (8a–q) are reported as non-steroidal GR antagonist. Compound 8g showed excellent h-GR binding and potent antagonistic activity (in vitro). The lead compound 8g exhibited significant oral antidiabetic and antihyperlipidemic effects (in vivo), along with liver selectivity. These preliminary results confirm discovery of potent and liver selective passive GR antagonist for the treatment of T2DM.
Mineralocorticoid receptor is involved in the regulation of genes responsible for hepatic glucose production
2006, Biochemical and Biophysical Research Communications
Citation Excerpt :
In addition, systemic GR blockade can be problematic in stress situations where increased cortisol levels are required. To overcome these issues, several attempts have been made to target GR antagonists such as RU-486 to liver [24]. Since RU-486 is also a progesterone antagonist used as an abortifacide, the pharmaceutical development path for these approaches is also challenging.
The mineralocorticoid receptor (MR) is expressed in kidney and plays a central role in the control of sodium, homeostatic fluid, and blood pressure. It has also been implicated in other functions in cardiovascular system, central nervous system, and adipose tissue. This study revealed a novel role of MR in the gene regulation related to hepatic glucose production. RNAi-mediated MR silencing led to a decrease in the expression of glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase, and fructose-1,6-bisphosphatase 1, the enzymes known to be involved in glucose production in liver. The MR-specific antagonists also down-regulated the expression of G6Pase, while the specific agonist enhanced G6Pase expression. These observations, for the first time, revealed a novel role for MR and its ligands in the regulation of de novo glucose synthesis in hepatocytes. It also suggests the potential of liver-specific MR modulation for the treatment of hyperglycemia.
Recent Advances in Therapeutic Approaches toType 2 Diabetes
2005, Annual Reports in Medicinal Chemistry
Bile acid conjugates of a nonsteroidal glucocorticoid receptor modulator
2004, Bioorganic and Medicinal Chemistry Letters
Optimization and metabolic stabilization of a class of nonsteroidal glucocorticoid modulators
2004, Bioorganic and Medicinal Chemistry Letters
Synthesis, activity, metabolic stability, and pharmacokinetics of glucocorticoid receptor modulator-statin hybrids
2004, Bioorganic and Medicinal Chemistry Letters
The synthesis, activity, metabolic stability, and pharmacokinetics of steroidal and nonsteroidal glucocorticoid receptor modulator–statin hybrids is reported. Potent steroidal antagonist–statin hybrids like 22 (h-GR binding IC₅₀=7 nM) and nonsteroidal modulator hybrids like 16 (h-GR binding IC₅₀=2 nM) were discovered. Appending a `statin'-like diol-acid group to the modulators dramatically improved metabolic stability (and in some cases hepatocyte activity), but did not impart hepatoselectivity.

View all citing articles on Scopus

View full text

An Evaluation of a C-Glucuronide as a liver targeting group: conjugate of a glucocorticoid antagonist

Abstract

J. Biol. Chem.

J. Am. Chem. Soc.

Curr. Med. Chem.

Endocrine Rev.

Physiol. Rev.

Diabetes

Endocrine Rev.

Ann. Reports Med. Chem.

J. Clin. Endocrinol. Metab.

J. Clin. Endocrinol. Metab.