XL335 is a potent and selective FXR agonist, also known under the synonyms FXR 450, Turofexorate isopropyl, and WAY-362450. This compound (CAS 629664-81-9) was originally discovered by Exelixis Pharmaceuticals, then licensed to Wyeth, now a wholly-owned subsidiary of Pfizer, where it carried the internal code PF-05294398. The XL335 molecular structure belongs to the azaindole class of non-steroidal FXR ligands, distinguishing it structurally from bile acid derivatives and isoxazole-based agonists developed by other groups.
Application of XL335
The farnesoid X receptor governs bile acid synthesis, lipid handling, and glucose metabolism in the liver and intestine, making it a frequent target in research on dyslipidemia, atherosclerosis, and fatty liver disease. The XL335 structure offers researchers a tool with high selectivity over related nuclear receptors, which matters because off-target activation of LXR or PPAR in the same assay would confound interpretation of FXR-specific effects. XL335 is highly selective versus other nuclear receptors such as LXR, PPAR, and ER, a profile that supports its continued use as a reference agonist in mechanistic FXR studies.
In Vitro
Turofexorate isopropyl is a potent, selective FXR agonist with an EC50 of 4 nM. It promotes transcription of human BSEP, human SHP, and mouse IBABP genes in reporter assays with EC50 values of 17, 230, and 33 nM respectively, and at a concentration of 1 μM it induces mRNA expression of BSEP, SHP, and IBABP in human cell cultures by 13-fold, 2-fold, and 20-fold. The compound binds to the ligand-binding domain of human FXR, occupying a predominantly hydrophobic pocket with only a few polar contacts.
In Vivo
Oral administration of WAY-362450 to LDLR-deficient mice lowers cholesterol and triglycerides, consistent with FXR's role in regulating bile acid feedback and lipid clearance pathways. In wild-type C57BL/6 mice, the FXR agonist attenuated lipopolysaccharide-induced serum amyloid P component and serum amyloid A3 mRNA levels in the liver, indicating an anti-inflammatory effect that extends beyond lipid metabolism alone. XL335 advanced to Phase I clinical trials for hyperlipidemia, though the program was ultimately discontinued.
Biochemical and Physiological Actions
WAY-362450 induces small heterodimer partner expression and represses cholesterol 7alpha-hydroxylase and sterol 12 alpha-hydroxylase, the two enzymes that control the rate-limiting steps of bile acid synthesis from cholesterol. This repression is the molecular basis for the compound's cholesterol-lowering effect observed in vivo: by activating FXR, XL335 chemical structure interactions with the receptor trigger a negative feedback loop that reduces hepatic bile acid output and shifts cholesterol toward other clearance pathways. The XL335 molecular weight and the broader pharmacophore captured by an XL335 chemical structure diagram help explain why this particular scaffold achieves such high FXR selectivity relative to earlier non-steroidal agonists.
Features and Benefits of XL335
What sets XL335 apart from other FXR tool compounds is the combination of single-digit nanomolar potency, oral bioavailability, and a documented selectivity margin over LXR, PPAR, and ER that has been independently confirmed across multiple research groups. Its well-characterized gene induction profile across BSEP, SHP, and IBABP gives researchers reliable pharmacodynamic markers for confirming FXR activation in new experimental systems, while its clinical-stage history in hyperlipidemia adds translational context rarely available for a pure research compound.
