Knocking on FXR's Door:The "Hammerhead"-Structure Series of FXRs Agonists - Amphiphilic Isoxazoles with Potent In Vitro and In Vivo Activities

Author(s): Christian Gege, Olaf Kinzel, Christoph Steeneck, Andreas Schulz, Claus Kremoser

Journal Name: Current Topics in Medicinal Chemistry

Volume 14 , Issue 19 , 2014

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Graphical Abstract:


The Farnesoid X Receptor (FXR) was recently validated in clinical studies using the bile acid analogue Obeticholic Acid (OCA) as an attractive drug target for liver diseases such as Primary Biliary Cirrhosis (PBC) or Non-alcoholic Steatohepatitis (NASH). OCA, however, turned out to induce cholesterol- related side effects upon prolonged treatment and it shows bile acid like pharmacokinetics. The quest for synthetic non-steroidal FXR agonists with general drug likeliness and improved pharmacokinetic and – dynamic properties has started more than a decade ago: The first non-steroidal and selective FXR agonist with decent submicromolar potency, GW4064, was patented in 1998 and published in 2000. Since then, many pharmaceutical companies have taken GW4064 as a structural template for their efforts in identifying novel patentable FXR agonists with the GW-derived trisubstituted isoxazole general structure. However, so far only one compound out of these different series has made it into the early stages of clinical development: The Px-102/Px-104 from Phenex is currently tested in a phase IIa study in patients with Non-Alcoholic Fatty Liver Disease (NAFLD). In this review we try to summarize from the patent and scientific literature the attempts to improve the GW4064 structure into different directions. Furthermore, we suggest directions for further improvements of this special class of synthetic FXR agonists which all display the typical “hammerhead”-conformation in the FXR ligand binding pocket that provides the basis for their impressive in vitro and in vivo potencies.

Keywords: Bile acid receptor, Farnesoid X receptor, FXR agonist, GW4064, Isoxazole, NAFLD, NASH, Px-102, PX20606.

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Article Details

Year: 2014
Page: [2143 - 2158]
Pages: 16
DOI: 10.2174/1568026614666141112094430
Price: $65

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