Research Article Details
| Article ID: | A03845 |
| PMID: | 33849361 |
| Source: | Expert Opin Drug Discov |
| Title: | The identification of farnesoid X receptor modulators as treatment options for nonalcoholic fatty liver disease. |
| Abstract: | INTRODUCTION: The farnesoid-x-receptor (FXR) is a ubiquitously expressed nuclear receptor selectively activated by primary bile acids. AREA COVERED: FXR is a validated pharmacological target. Herein, the authors review preclinical and clinical data supporting the development of FXR agonists in the treatment of nonalcoholic fatty liver disease. EXPERT OPINION: Development of systemic FXR agonists to treat the metabolic liver disease has been proven challenging because the side effects associated with these agents including increased levels of cholesterol and LDL-c and reduced HDL-c raising concerns over their long-term cardiovascular safety. Additionally, pruritus has emerged as a common, although poorly explained, dose-related side effect with all FXR ligands, but is especially common with OCA. FXR agonists that are currently undergoing phase 2/3 trials are cilofexor, tropifexor, nidufexor and MET409. Some of these agents are currently being developed as combination therapies with other agents including cenicriviroc, a CCR2/CCR5 inhibitor, or firsocostat an acetyl CoA carboxylase inhibitor. Additional investigations are needed to evaluate the beneficial effects of combination of these agents with statins. It is expected that in the coming years, FXR agonists will be developed as a combination therapy to minimize side effects and increase likelihood of success by targeting different metabolic pathways. |
| DOI: | 10.1080/17460441.2021.1916465 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs |
|---|
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T24 | C-C chemokine receptor type 2 | CCR2 | antagonist | GPCR | P41597 | CCR2_HUMAN | Details |
| T17 | Farnesoid X-activated receptor | NR1H4 | agonist | Nuclear hormone receptor | Q96RI1 | NR1H4_HUMAN | Details |
| T25 | C-C chemokine receptor type 5 | CCR5 | antagonist | GPCR | P51681 | CCR5_HUMAN | Details |
| T07 | Bile acid receptor | NR1H4 | agonist | Nuclear hormone receptor | Q96RI1 | NR1H4_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class |
|---|
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D068 | Cenicriviroc | Chemical drug | DB11758 | CCR2 inhibitor; CCR5 inhibitor | Anti-fibrosis | Failed in clinical trials | Details |
| D136 | Firsocostat | Chemical drug | DB16166 | ACC inhibitor | Enhance lipid metabolism | Under clinical trials | Details |
| D203 | Levothyroxine | Chemical drug | DB00451 | THRA agonist; THRB agonist | Anti-fibrosis | Under clinical trials | Details |
| D078 | Cilofexor | Chemical drug | DB15168 | FXR agonist | Enhance lipid metabolism | Under clinical trials | Details |
| D239 | Niacin | Supplement | DB00627 | NNMT binder | Hypolipidemic drug | Under clinical trials | Details |
| D241 | Nidufexor | Chemical drug | DB16255 | FXR modulator | Enhance lipid metabolism | Under clinical trials | Details |
| D248 | Obeticholic Acid | Chemical drug | DB05990 | NR1H4 activator; NR1H4 agonist; FXR agonist | Enhance lipid metabolism | Approval rejected | Details |
| D379 | Tropifexor | Chemical drug | DB16343 | FXR agonist | Enhance lipid metabolism | Under clinical trials | Details |
| D349 | Statins | Miscellany | -- | -- | -- | Under clinical trials | Details |