Cilofexor

Product NameCilofexor
CAS1418274-28-8
MFC28H22Cl3N3O5
MW586.85
EINECS
MOL File1418274-28-8.mol

Chemical Properties

Boiling point	855.5±65.0 °C(Predicted)
Density	1.538±0.06 g/cm3(Predicted)
storage temp.	Store at -20°C
solubility	DMSO:32.5(Max Conc. mg/mL);55.38(Max Conc. mM)
form	A crystalline solid
pka	2.10±0.10(Predicted)
color	Off-white to light yellow
InChIKey	KZSKGLFYQAYZCO-UHFFFAOYSA-N
SMILES	C1(N2CC(C3=CC=C(OCC4=C(C5CC5)ON=C4C4=C(Cl)C=CC=C4Cl)C=C3Cl)(O)C2)=NC=CC(C(O)=O)=C1

Usage And Synthesis

Description

Cilofexor inhibits binding of a synthetic peptide, comprising residues 676-700 of the steroid receptor coactivator 1 (SRC-1), to the farnesoid X receptor (FXR; EC₅₀ = <25 nM in a FRET activity assay). It has FXR agonist activity in a mammalian one hybrid (M1H) assay (EC₅₀ = ≥100 nM).

Uses

Cilofexor (GS-9674) is a potent, selective and orally active nonsteroidal FXR agonist with an EC50 of 43 nM. Cilofexor has anti-inflammatory and antifibrotic effects. Cilofexor has the potential for primary sclerosing cholangitis (PSC) and nonalcoholic steatohepatitis (NASH) research[1][2].

in vivo

Cilofexor (GS-9674; 30 mg/kg; oral gavage; once daily; for 10 weeks; male Wistar rats) treatment significantly increases Fgf15 expression in the ileum and decreased Cyp7a1 in the liver in nonalcoholic steatohepatitis (NASH) rats. Liver fibrosis and hepatic collagen expression are significantly reduced. Cilofexor also significantly reduces hepatic stellate cell (HSC) activation and significantly decreases portal pressure, without affecting systemic hemodynamics^[3].

Animal Model:	Male Wistar rats received a choline-deficient high fat diet (CDHFD)^[3]
Dosage:	30 mg/kg
Administration:	Oral gavage; once daily; for 10 weeks
Result:	Significantly increased Fgf15 expression in the ileum and decreased Cyp7a1 in the liver. Liver fibrosis and hepatic collagen expression were significantly reduced.

References

[1] Trauner M, et al. The Nonsteroidal Farnesoid X Receptor Agonist Cilofexor (GS-9674) Improves Markers of Cholestasis and Liver Injury in Patients With Primary Sclerosing Cholangitis. Hepatology. 2019 Sep;70(3):788-801. DOI:10.1002/hep.30509
[2] Patel K, et al. Cilofexor, a Nonsteroidal FXR Agonist, in Non-Cirrhotic Patients with Nonalcoholic Steatohepatitis: A Phase 2 Randomized Controlled Trial. Hepatology. 2020 Mar 1. DOI:10.1002/hep.31205
[3] P. Schwab, et al. The FXR agonist GS-9674 reduces fibrosis and portal hypertension in a rat model of NASH. April 2018,Volume 68, Supplement 1, Pages S471-S472.

Cilofexor

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