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

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.

Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease

“…GS-9674, a synthetic non-steroidal FXR agonist, is currently in a phase I study. In contrast to OCA, GS-9674 and similar agents are less likely to undergo enterohepatic circulation and may have more predictable pharmacokinetics 42. INT-767 is a bile acid analogue that acts as a dual agonist on FXR and on TGR5, the transmembrane G-protein bile acid receptor.…”

Selective Optimization of Pranlukast to Farnesoid X Receptor Modulators

“…FXR activation proved effective at decreasing hepatic steatosis and fibrosis, revealed anti‐diabetic activity and has anti‐inflammatory properties . Currently, several FXR agonists such as the steroid obeticholic acid ( 2 ) and derivatives of the widely used reference compound GW4064 ( 3 ) are studied in clinical trials for the treatment of NASH. However, full FXR agonists may cause marked adverse effects by repressing cholesterol 7α‐hydroxylase (CYP7A1) which leads to loss of metabolic cholesterol elimination .…”

Farnesoid X receptor modulators (2011 – 2014): a patent review

“…As evidenced by the above discussion and by the previous published reviews [25,44,45], during the past years wide medicinal chemistry protocols have been carried out in order to identify and to develop potent and selective ligands targeting FXR. Many of these ligands have agonistic activity and have been largely used as tools to dissect FXR biology and FXR regulated signaling and transcriptional events.…”

“…Thus, several groups from academy and industry have harnessed the chemical space around the stilbene moiety, the position of the carboxyl group on the terminal aryl unit, the nature of classical chlorophenyl linker, whereas the central isoxazole core, with the isopropyl group at C-5 and the 2,6-dihalogen-substituted phenyl moiety at C-3, has been conserved. All related patent applications date before the year 2010 and have been largely reviewed in previous contributes [25,44,45].…”