Danifexor

CAS 2648738-68-3

MF C29H20Cl2N2O5 MW547.386

6-[6-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]naphthalen-2-yl]oxypyridine-3-carboxylic acid

3-Pyridinecarboxylic acid, 6-[[6-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methoxy]-2-naphthalenyl]oxy]-

farnesoid X receptor agonist, TUU8G1CX9O, HEC 96719, ASC42 

Danifexor is an investigational drug that acts as a potent and selective agonist for the farnesoid X receptor (FXR). It was primarily being developed for the treatment of liver diseases such as Primary Biliary Cholangitis (PBC). ProbeChem +1

However, recent reports from April 2024 indicate that development for Danifexor has been discontinued because it was deemed non-competitive against other emerging therapies for PBC. 

Key Properties and Identifiers

Danifexor is a non-steroidal molecule with specific chemical markers used in laboratory research:

• Target: Farnesoid X receptor (FXR).

Therapeutic Context

The drug was designed to target the FXR pathway, which regulates bile acid, lipid, and glucose metabolism. 

• Primary Goal: Treatment of Primary Biliary Cholangitis (PBC), a chronic liver disease.
• Mechanism: As an agonist, it binds to and activates FXR to help reduce the toxic buildup of bile acids in the liver.

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US380594531&_cid=P21-MOAUR7-95920-1

Example 1

Preparation of 6-((6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methoxy)naphthalen-2-yl)oxy)nicotinic acid (Compound 1)

(a) Referring to the following reaction equation (Route A), Compound 1A-1 (1.0 g, 2.88 mmol, 1 eq.), Compound 1A-2 (0.46 g, 2.88 mmol, 1 eq.) and cesium carbonate (1.88 g, 5.76 mmol, 2 eq.) were dissolved in DMF (10 ml). The reaction was carried out at 65° C. for 2 h. After cooling, 10 ml water and 10 ml EA (ethyl acetate) were added for extraction, and the organic phase was washed with water and concentrated to dryness to give Compound 1A, 6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)naphthalen-2-ol, 0.8 g, yield: 65.0%. LCMS (ESI): calculated for C ₂₃H ₁₇C ₁₂NO ₃; [M+H] ⁺: 426.1, found: 426.1.

b) Referring to the following reaction equation, Compound 1A (0.2 g, 0.47 mmol, 1 eq.), 6-bromonicotinic acid methyl ester (0.1 g, 0.47 mmol, 1 eq.) and cesium carbonate (0.306 g, 0.94 mmol, 2 eq.) were dissolved in DMF (10 ml). The reaction was carried out at 65° C. for 2 h. After cooling, 10 ml water and 10 ml EA were added for extraction, and the organic phase was washed with water and concentrated to dryness to give Compound 1B, methyl 6((6((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)naphthalene-2-yl)oxy)nicotinate, 0.21 g, yield: 80.0%. LCMS (ESI): calculated for C ₃₀H ₂₂C ₁₂N ₂O ₅; [M+H] ⁺: 561.1, found: 561.1.

(c) Referring to the following reaction equation, compound 1B (100 mg) was dissolved in methanol (2 ml), then 10% NaOH aqueous solution (1 ml) was added, the temperature was raised to 60° C., and the reaction was carried out for 1 h. The pH of the reaction solution was adjusted to 2 to 4 by adding 1N HCl solution, and 10 ml EA (ethyl acetate) was added for extraction. The organic phase was concentrated and purified on a column (PE/EA/AcOH=1/1/01 elution, wherein PE is petroleum ether) to give the title compound 1 (36 mg, yield: 37.0%).

1H NMR (400 MHz, DMSO-d 6) δ 8.57 (s, 1H), 8.23 (d, J=7.2 Hz, 1H), 7.74 (dd, J=2.0, 8.8 Hz, 2H), 7.60 (d, J=7.6 Hz, 2H), 7.56 (s, 1H), 7.51 (dd, J=8.8, 7.2 Hz, 1H), 7.33 (s, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.93 (d, J=6.4 Hz, 1H), 4.98 (s, 2H), 2.57-2.50 (m, 1H), 1.19-1.11 (m, 4H). LCMS (ESI): calculated for C 29H 20Cl 2N 2O 5; [M+H] +: 547.1, found: 547.1. 13C NMR (400 MHz, DMSO-d 6) δ7.79, 8.87, 8.87, 59.31, 107.74, 110.05, 110.97, 117.64, 119.43, 122.52, 127.55, 128.64, 128.89, 128.89, 129.18, 129.67, 131.73, 131.79, 132.94, 135.10, 135.10, 141.20, 149.11, 150.73, 155.79, 159.68, 163.82, 167.81, 172.61. IR (cm −1): major stretches at 1591.94 (C═O stretch), 1412.27, 1556.70 (C—C stretch), 1364.37, 1389.89 (C—H deformation), 1218.41, 1250.94 (C═N stretch), 791.88 (C—Cl stretch).

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021109712&_cid=P21-MOAUXW-99264-1

PAT

• Use and pharmaceutical composition of phenylisoxazolyl methylene-naphthalene-ether derivativesPublication Number: WO-2021109713-A1Priority Date: 2019-12-03
• Compounds for modulating activity of fxr and uses thereofPublication Number: WO-2021109712-A1Priority Date: 2019-12-03
• Uses and pharmaceutical compositions of phenylisoxazolylmethylene-naphthalene-ether derivativesPublication Number: CN-112891348-APriority Date: 2019-12-03
• Compounds that modulate FXR activity and their applicationsPublication Number: CN-112898289-APriority Date: 2019-12-03
• Compounds that modulate FXR activity and their applicationsPublication Number: CN-112898289-BPriority Date: 2019-12-03Grant Date: 2022-11-04
• Uses and pharmaceutical compositions of phenylisoxazolyl methylene-naphthalene-ether derivativesPublication Number: KR-20220101697-APriority Date: 2019-12-03
• Compounds for modulating activity of fxr and uses thereofPublication Number: EP-4073070-A1Priority Date: 2019-12-03
• Use and pharmaceutical composition of phenylisoxazolyl methylene-naphthalene-ether derivativesPublication Number: EP-4073071-A1Priority Date: 2019-12-03
• Compounds for modulating activity of fxr and uses thereofPublication Number: WO-2021108974-A1Priority Date: 2019-12-03

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References

////////danifexor, ANAX LAB, farnesoid X receptor agonist, TUU8G1CX9O, HEC 96719, ASC42