Tropifexor

Tropifexor is an investigational drug which acts as an agonist of the farnesoid X receptor (FXR). It was discovered by researchers from Novartis and Genomics Institute of the Novartis Research Foundation. Its synthesis and pharmacological properties were published in 2017.[1] It was developed for the treatment of cholestatic liver diseases and nonalcoholic steatohepatitis (NASH). In combination with cenicriviroc, a CCR2 and CCR5 receptor inhibitor, it is undergoing a phase II clinical trial for NASH and liver fibrosis.[2]

Tropifexor

Clinical data
ATC code	None
Identifiers
IUPAC name 2-[(1R,5S)-3-[[5-Cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid
CAS Number	1383816-29-2
PubChem CID	121418176
UNII	NMZ08KM76Z
KEGG	D11548
Chemical and physical data
Formula	C29H25F4N3O5S
Molar mass	603.59 g·mol^−1
3D model (JSmol)	Interactive image
SMILES C1C[C@H]2CC(C[C@@H]1N2C3=NC4=C(C=C(C=C4S3)C(=O)O)F)OCC5=C(ON=C5C6=CC=CC=C6OC(F)(F)F)C7CC7
InChI InChI=1S/C29H25F4N3O5S/c30-21-9-15(27(37)38)10-23-25(21)34-28(42-23)36-16-7-8-17(36)12-18(11-16)39-13-20-24(35-41-26(20)14-5-6-14)19-3-1-2-4-22(19)40-29(31,32)33/h1-4,9-10,14,16-18H,5-8,11-13H2,(H,37,38)/t16-,17+,18+ Key:VYLOOGHLKSNNEK-PIIMJCKOSA-N

Rats treated orally with tropifexor (0.03 to 1 mg/kg) showed an upregulation of the FXR target genes, BSEP and SHP, and a down-regulation of CYP8B1. Its EC50 for FXR is between 0.2 and 0.26 nM depending on the biochemical assay.

The patent which covers tropifexor and related compounds was published in 2010.[3]

References

1. Tully DC, Rucker PV, Chianelli D, Williams J, Vidal A, Alper PB, et al. (December 2017). "Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH)". Journal of Medicinal Chemistry. 60 (24): 9960–9973. doi:10.1021/acs.jmedchem.7b00907. PMID 29148806.
2. Clinical trial number NCT03517540 for "Safety, Tolerability, and Efficacy of a Combination Treatment of Tropifexor (LJN452) and Cenicriviroc (CVC) in Adult Patients With Nonalcoholic Steatohepatitis (NASH) and Liver Fibrosis. (TANDEM)" at ClinicalTrials.gov
3. WO Application Filing 2012087519, Alper PB, Chianelli D, Mutnick D, Vincent P, Tully DC, "Compositions and methods for modulating fxr", published 2012-06-28, assigned to Genomics Institute of the Novartis Research Foundation. Retrieved 17 May 2019.