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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