Synthesis and pharmacological validation of a novel series of non-steroidal FXR agonists

Intestinal Farnesoid X Receptor Controls Transintestinal Cholesterol Excretion in Mice

“…21 PX was shown previously to potently decrease plasma cholesterol levels and progression of atherosclerosis in cholesteryl ester transfer protein (CETP)-transgenic/low-density lipoprotein (LDL)-receptor knock-out mice. 22 At first sight, our results indicate that mobilization of cholesterol, driven by increased TICE, may explain the cholesterol-lowering effect in plasma.…”

“…When stated, mice received 10 mg/kg/day PX20606 (PX) (Phenex Pharmaceuticals, AG, Heidelberg, Germany) 21,22 , 0.005% (w/w) ezetimibe (Ezetrol; Pharmacy UMCG, Groningen, The Netherlands), or both compounds mixed into their diet. Additionally, ABCG8 KO mice were injected with 1 x 10 11 particles/mouse of an Abcg8-encoding adenovirus (AdABCG8) or control virus (AdNull) and experiments were performed between day 3 and day 5 after administration.…”

Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease

“…Thus, quite an effort has been made to develop GW4064 analogs with comparable potency and improved biological compatibility ( 116,117 ); however, none has yet passed preclinical testing. In addition, a number of GW4064 analogs are handled by BA transporters and conjugated like BA, leading to very low plasma levels and hepatic accumulation ( 118 ).…”

Synthetic Farnesoid X Receptor Agonists Induce High-Density Lipoprotein-Mediated Transhepatic Cholesterol Efflux in Mice and Monkeys and Prevent Atherosclerosis in Cholesteryl Ester Transfer Protein Transgenic Low-Density Lipoprotein Receptor (−/−) Mice

“…were synthesized according to published synthesis protocols (Maloney et al, 2000;Pellicciari et al, 2002;Mehlmann et al, 2009;Abel et al, 2010) and checked for identity and purity by 1 H-NMR and liquid chromatography/mass spectrometry before being tested in FXR activity assays. Synthesis of PX20606 has been described previously (Kremoser et al, 2011).…”

“…1) were evaluated for their plasma lipid-lowering capabilities in C57BL/6J mice on a high-fat diet regimen. PX20350 (Abel et al, 2010) and PX20606 are structurally related to GW4064, whereas FXR-450 represents a structurally diverse chemotype of a nonsteroidal, fully synthetic FXR agonist. 6-ECDCA is closely related to the natural FXR ligand chenodeoxycholic acid albeit with higher potency at the human FXR compared with its natural counterpart (Tables 1 and 2).…”