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更新于：2025-01-27
Vonafexor
更新于：2025-01-27
概要
基本信息
结构/序列
分子式C19H15Cl3N2O5S |
InChIKeyXLGQSYUNOIJBNR-UHFFFAOYSA-N |
CAS号1192171-69-9 |
关联
15
项与 Vonafexor 相关的临床试验CTIS2023-509638-20-00
Vonafexor fixed dose-escalation safety and proof-of-concept study in patients with at risk of progression Alport syndrome - EYP001-208
NCT06425055
Vonafexor Fixed Dose-escalation Safety and Proof-of-concept Study in Patients with At Risk of Progression Alport Syndrome
CTIS2023-509192-16-00
A study to Assess the Effect of Vonafexor on Kidney Function in Subjects With Impaired Renal Function and Suspected MASH - EYP001-210
100 项与 Vonafexor 相关的临床结果
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100 项与 Vonafexor 相关的转化医学
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100 项与 Vonafexor 相关的专利（医药）
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7
项与 Vonafexor 相关的文献（医药）2023-04-01European journal of medicinal chemistry
Machine learning- and structure-based discovery of a novel chemotype as FXR agonists for potential treatment of nonalcoholic fatty liver disease
Article
作者: Zhang, Wenxuan ; Shen, Zhufang ; Xia, Jie ; Qin, Tong ; Feng, Jing ; Hu, Yuhua ; Lei, Lei ; Zhang, Liangren ; Liu, Zhenming ; Huan, Yi ; Wu, Song ; Gao, Xuefeng
Farnesoid X receptor (FXR) is a promising target for drug discovery against nonalcoholic fatty liver disease (NAFLD). However, no FXR agonist has been approved for NAFLD so far. The R & D of FXR agonists are somewhat hindered by the lack of effective and safe chemotypes. To this end, we developed a multi-stage computational workflow to screen the Specs and ChemDiv chemical library for FXR agonists, which consisted of machine learning (ML)-based classifiers, shape-based and electrostatic-based models, a FRED-based molecular docking protocol, an ADMET prediction protocol and substructure search. As a result, we identified a novel chemotype that has never been reported before, with compound XJ02862 (ChemDiv ID: Y020-6413) as the representative. By designing an asymmetric synthesis strategy, we were able to prepare four isomers of compound XJ02862. Interestingly, one of the isomers, 2-((S)-1-((2S,4R)-2-methyl-4-(phenylamino)-3,4-dihydroquinolin-1(2H)-yl)-1-oxopropan-2-yl)hexahydro-1H-isoindole-1,3(2H)-dione (XJ02862-S2), showed potent FXR agonistic activity in HEK293T cells. The molecular docking, molecular dynamics simulations and site-directed mutagenesis suggested the hydrogen bond between compound XJ02862-S2 and HIS294 of FXR is essential for ligand binding. We further demonstrated that compound XJ02862-S2 had no agonistic effect on TGR5. Further biological experiments have shown that compound XJ02862-S2 could ameliorate hypercholesterolemia, hepatic steatosis, hyperglycemia, insulin resistance (IR) in high-fat-diet induced obese (DIO) mice. In term of molecular mechanism, compound XJ02862-S2 regulates the expression of FXR downstream genes involved in lipogenesis, cholesterol transport and bile acid biosynthesis and transport. Taken together, we have discovered a novel chemotype as potent FXR agonists for NAFLD by computational modeling, chemical synthesis and biological evaluation.
2023-03-01Journal of hepatology
Hepatic and renal improvements with FXR agonist vonafexor in individuals with suspected fibrotic NASH
Article
作者: Darteil, Raphaël ; Harrison, Stephen A ; Lawitz, Eric ; Alkhouri, Naim ; Francque, Sven ; Bureau, Christophe ; Vonderscher, Jacky ; Sanyal, Arun ; Scalfaro, Pietro ; Abdelmalek, Manal ; Wolf, Myles ; Loustaud-Ratti, Véronique ; Girma, Hugo ; Couchoux, Harold ; Ratziu, Vlad
BACKGROUND & AIMS:
The LIVIFY trial investigated the safety, tolerability, and efficacy of vonafexor, a second-generation, non-bile acid farnesoid X receptor agonist in patients with suspected fibrotic non-alcoholic steatohepatitis (NASH).
METHODS:
This double-blind phase IIa study was conducted in two parts. Patients were randomised (1:1:1:1) to receive placebo, vonafexor 100 mg twice daily (VONA-100BID), vonafexor 200 mg once daily (VONA-200QD), or 400 mg vonafexor QD (VONA-400QD) in Part A (safety run-in, pharmacokinetics/pharmacodynamics) or placebo, vonafexor 100 mg QD (VONA-100QD), or VONA-200QD (1:1:1) in Part B. The primary efficacy endpoint was a reduction in liver fat content (LFC) by MRI-proton density fat fraction, while secondary endpoints included reduced corrected T1 values and liver enzymes, from baseline to Week 12.
RESULTS:
One hundred and twenty patients were randomised (Part A, n = 24; Part B, n = 96). In Part B, there was a significant reduction in least-square mean (SE) absolute change in LFC from baseline to Week 12 for VONA-100QD (-6.3% [0.9]) and VONA-200QD (-5.4% [0.9]), vs. placebo (-2.3% [0.9], p = 0.002 and 0.012, respectively). A >30% relative LFC reduction was achieved by 50.0% and 39.3% of patients in the VONA-100QD and VONA-200QD arms, respectively, but only in 12.5% in the placebo arm. Reductions in body weight, liver enzymes, and corrected T1 were also observed with vonafexor. Creatinine-based glomerular filtration rate improved in the active arms but not the placebo arm. Mild to moderate generalised pruritus was reported in 6.3%, 9.7%, and 18.2% of participants in the placebo, VONA-100QD, and VONA-200QD arms, respectively.
CONCLUSIONS:
In patients with suspected fibrotic NASH, vonafexor was safe and induced potent liver fat reduction, improvement in liver enzymes, weight loss, and a possible renal benefit.
CLINICAL TRIAL NUMBER (EUDRACT):
2018-003119-22.
CLINICALTRIALS:
GOV IDENTIFIER:
NCT03812029.
IMPACT AND IMPLICATIONS:
Non-alcoholic steatohepatitis (NASH) has become a leading cause of chronic liver disease worldwide. Affected patients are also at higher risk of developing chronic kidney disease. There are no approved therapies and only few options to treat this population. The phase IIa LIVIFY trial results show that single daily administration of oral vonafexor, an FXR agonist, leads in the short term to a reduction in liver fat, liver enzymes, fibrosis biomarkers, body weight and abdominal circumference, and a possible improvement in kidney function, while possible mild moderate pruritus (a peripheral FXR class effect) and an LDL-cholesterol increase are manageable with lower doses and statins. These results support exploration in longer and larger trials, with the aim of addressing the unmet medical need in NASH.
2023-03-01Biochemical pharmacology
Pharmacological characterization of second generation FXR agonists as effective EphA2 antagonists: A successful application of target hopping approach
Article
作者: Giorgio, Carmine ; Lodola, Alessio ; Galvani, Francesca ; Zappia, Alfonso ; Mor, Marco ; Barocelli, Elisabetta ; Ballabeni, Vigilio ; Bertoni, Simona ; Scalvini, Laura ; Tognolini, Massimiliano ; Ferrari, Francesca Romana
It is well demonstrated the key role of Eph-ephrin system, specifically of EphA2 receptor, in supporting tumor growth, invasion, metastasis and neovascularization. We previously identified FXR agonists as eligible antagonists of Eph-ephrin system. Herein we characterize new commercially available FXR (Farnesoid X Receptor) agonists as potential Eph ligands including Cilofexor, Nidufexor, Tropifexor, Turofexorate isopropyl and Vonafexor. Our exploration based on molecular modelling investigations and binding assays shows that Cilofexor binds specifically and reversibly to EphA2 receptor with a Ki value in the low micromolar range. Furthermore, Cilofexor interferes with the phosphorylation of EphA2 and the cell retraction and rounding in PC3 prostate cancer cells, both events depending on EphA2 activation. In conclusion, we can confirm that target hopping can be a successful approach to discover new moiety of protein-protein inhibitors.
100 项与 Vonafexor 相关的药物交易
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研发状态
10 条进展最快的记录, 后查看更多信息
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| Alport 综合征 | 临床2期 | 美国 |  ENYO Pharma SA初创企业 | 2024-08-01 |
| Alport 综合征 | 临床2期 | 法国 | ENYO Pharma SA初创企业 | 2024-08-01 |
| Alport 综合征 | 临床2期 | 西班牙 | ENYO Pharma SA初创企业 | 2024-08-01 |
| 慢性乙型肝炎 | 临床2期 | 澳大利亚 | ENYO Pharma SA初创企业 | 2020-05-12 |
| 慢性乙型肝炎 | 临床2期 | 中国香港 | ENYO Pharma SA初创企业 | 2020-05-12 |
| 慢性乙型肝炎 | 临床2期 | 波兰 | ENYO Pharma SA初创企业 | 2020-05-12 |
| 慢性乙型肝炎 | 临床2期 | 韩国 | ENYO Pharma SA初创企业 | 2020-05-12 |
| 非酒精性脂肪性肝炎 | 临床2期 | 美国 | ENYO Pharma SA初创企业 | 2019-01-30 |
| 非酒精性脂肪性肝炎 | 临床2期 | 比利时 | ENYO Pharma SA初创企业 | 2019-01-30 |
| 非酒精性脂肪性肝炎 | 临床2期 | 法国 | ENYO Pharma SA初创企业 | 2019-01-30 |
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临床结果
临床结果
适应症
分期
评价
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临床2期 | 120 | Placebo (Placebo Part B) | 獵鬱衊繭鬱築簾積艱糧(鏇簾願遞鑰網夢觸醖壓) = 網遞蓋製糧顧鏇構窪齋 製壓艱艱範壓夢壓鏇窪 (觸製蓋壓鏇網願壓願範, 醖廠衊鏇繭餘繭淵夢衊 ~ 觸糧淵選築壓憲夢鹽壓) 更多 | - | 2023-05-06 | ||
(Vonafexor 100 mg QD Part B) | 獵鬱衊繭鬱築簾積艱糧(鏇簾願遞鑰網夢觸醖壓) = 壓網襯醖壓壓顧築餘蓋 製壓艱艱範壓夢壓鏇窪 (觸製蓋壓鏇網願壓願範, 網窪鏇鹽齋遞鬱鹽鏇糧 ~ 糧繭獵顧餘築鹹網鏇製) 更多 | ||||||
临床2期 | 26 | Nucleotide analogue (Entecavir or Tenofovir Disoproxil)+EYP001a (Experimental Arm) | 積鏇範憲蓋範夢壓蓋餘(願網夢願餘壓網構獵構) = 憲簾蓋觸醖壓鏇齋鏇淵 築膚製繭壓餘艱蓋齋窪 (鹹醖獵鏇網淵繭艱製襯, 廠範鏇範願觸齋築醖鬱 ~ 淵衊齋製艱構遞築廠顧) 更多 | - | 2022-10-12 | ||
Nucleotide analogue (Entecavir or Tenofovir Disoproxil) (Control Arm) | 積鏇範憲蓋範夢壓蓋餘(願網夢願餘壓網構獵構) = 糧憲簾衊構糧壓選鹽願 築膚製繭壓餘艱蓋齋窪 (鹹醖獵鏇網淵繭艱製襯, 鏇齋顧窪廠夢齋淵積蓋 ~ 鬱積製鑰繭獵鏇築淵鑰) 更多 | ||||||
临床2期 | 20 | 繭夢鹽醖廠積憲獵繭衊(遞廠獵選醖艱糧膚糧鑰) = 糧築憲鬱壓築糧網壓願 願積憲鏇膚淵壓範淵顧 (醖選鬱願糧鬱獵齋選襯 ) | 积极 | 2021-07-30 | |||
繭夢鹽醖廠積憲獵繭衊(遞廠獵選醖艱糧膚糧鑰) = 選願鏇積獵蓋廠網鬱淵 願積憲鏇膚淵壓範淵顧 (醖選鬱願糧鬱獵齋選襯 ) | |||||||
N/A | - | - | 製壓糧築淵積廠齋鏇網(觸顧觸積餘製簾膚繭製) = FGF19 protein was also stimulated significantly by EYP001 積簾糧顧選選鬱壓壓夢 (蓋構網獵糧醖選鑰窪蓋 ) | - | 2019-10-01 |
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