Ervogastat
(Synonyms: (S)-2-(5-((3-乙氧基吡啶-2-基]氧基]吡啶-3-基)-N-(四氢呋喃-3-基)嘧啶-5-甲酰胺) 目录号 : GC62428
Ervogastat (PF-06865571, DGAT2i) is a potent diacylglycerol acyltransferase 2 (DGAT2) inhibitor that reduces steatosis and hepatic triglyceride levels in non-alcoholic steatohepatitis (NASH).
Cas No.:2186700-33-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Ervogastat (PF-06865571, DGAT2i) is a potent diacylglycerol acyltransferase 2 (DGAT2) inhibitor that reduces steatosis and hepatic triglyceride levels in non-alcoholic steatohepatitis (NASH).
[1] KyeongJin Kim, et al.Int J Mol Sci. 2020 Mar 26;21(7):2296.
| Cas No. | 2186700-33-2 | SDF | |
| 别名 | (S)-2-(5-((3-乙氧基吡啶-2-基]氧基]吡啶-3-基)-N-(四氢呋喃-3-基)嘧啶-5-甲酰胺 | ||
| 分子式 | C21H21N5O4 | 分子量 | 407.42 |
| 溶解度 | DMSO : 125 mg/mL (306.81 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4545 mL | 12.2723 mL | 24.5447 mL |
| 5 mM | 0.4909 mL | 2.4545 mL | 4.9089 mL |
| 10 mM | 0.2454 mL | 1.2272 mL | 2.4545 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Efficacy and safety of an orally administered DGAT2 inhibitor alone or coadministered with a liver-targeted ACC inhibitor in adults with non-alcoholic steatohepatitis (NASH): rationale and design of the phase II, dose-ranging, dose-finding, randomised, placebo-controlled MIRNA (Metabolic Interventions to Resolve NASH with fibrosis) study
BMJ Open 2022 Mar 30;12(3):e056159.PMID:35354614DOI:10.1136/bmjopen-2021-056159.
Introduction: Small molecule inhibitors of the terminal step in intrahepatic triglyceride synthesis (diacylglycerol acyltransferase 2 inhibitor (DGAT2i, PF-06865571, Ervogastat)) and upstream blockade of de novo lipogenesis via acetyl-coenzyme A carboxylase inhibitor (ACCi, PF-05221304, clesacostat) showed promise in reducing hepatic steatosis in early clinical trials. This study assesses efficacy and safety of these metabolic interventions to resolve non-alcoholic steatohepatitis (NASH) with fibrosis. Methods and analysis: This phase II, randomised, dose-ranging, dose-finding study evaluates DGAT2i 25-300 mg two times per day (BID) or 150-300 mg once a day, DGAT2i 150-300 mg BID+ACCi 5-10 mg BID coadministration or matching placebo in a planned 450 adults with biopsy-confirmed NASH and liver fibrosis stages 2-3 from approximately 220 sites in 11 countries across North America, Europe and Asia. A triage approach including double-confirmation via non-invasive markers is included prior to screening/baseline liver biopsy. On confirmation of histological diagnosis, participants enter a ≥6-week run-in period, then a 48-week double-blind, double-dummy dosing period. The primary endpoint is the proportion of participants achieving histological NASH resolution without worsening fibrosis, ≥1 stage improvement in fibrosis without worsening NASH, or both, assessed by central pathologists. Other endpoints include assessment of hepatic steatosis (imaging substudy), overall safety and tolerability, and evaluation of blood-based biomarkers and quantitative ultrasound parameters over time. Ethics and dissemination: Metabolic Interventions to Resolve NASH with fibrosis (MIRNA) is conducted in accordance with the Declaration of Helsinki and Council for International Organisations of Medical Sciences (CIOMS) International Ethical Guidelines, International Council on Harmonisation Good Clinical Practice guidelines, applicable laws and regulations, including privacy laws. Local independent review board/ethics committees (IRB/ECs) review/approve the protocol, any amendments, informed consent and other forms. Participants provide written informed consent. Details of all IRB/ECs, as well as results, will be published in a peer-reviewed journal and publicly disclosed through ClinicalTrials.gov, EudraCT, and/or www.pfizer.com and other public registries as per applicable local laws/regulations. Trial registration number: NCT04321031.
Discovery of Ervogastat (PF-06865571): A Potent and Selective Inhibitor of Diacylglycerol Acyltransferase 2 for the Treatment of Non-alcoholic Steatohepatitis
J Med Chem 2022 Nov 24;65(22):15000-15013.PMID:36322383DOI:10.1021/acs.jmedchem.2c01200.
Discovery efforts leading to the identification of Ervogastat (PF-06865571), a systemically acting diacylglycerol acyltransferase (DGAT2) inhibitor that has advanced into clinical trials for the treatment of non-alcoholic steatohepatitis (NASH) with liver fibrosis, are described herein. Ervogastat is a first-in-class DGAT2 inhibitor that addressed potential development risks of the prototype liver-targeted DGAT2 inhibitor PF-06427878. Key design elements that culminated in the discovery of Ervogastat are (1) replacement of the metabolically labile motif with a 3,5-disubstituted pyridine system, which addressed potential safety risks arising from a cytochrome P450-mediated O-dearylation of PF-06427878 to a reactive quinone metabolite precursor, and (2) modifications of the amide group to a 3-THF group, guided by metabolite identification studies coupled with property-based drug design.
The Postnatal Resolution of Developmental Toxicity Induced by Pharmacological Diacylglycerol Acyltransferase 2 (DGAT2) Inhibition During Gestation in Rats
Toxicol Sci 2022 Sep 24;189(2):225-236.PMID:35866640DOI:10.1093/toxsci/kfac077.
Ervogastat (PF-06865571) is a small molecule diacylglycerol acyltransferase 2 (DGAT2) inhibitor being developed for the oral treatment of nonalcoholic steatohepatitis (NASH) with liver fibrosis. DGAT2 is a key enzyme in triglyceride synthesis in tissues and in regulating energy metabolism. Fertility and developmental toxicity studies with Ervogastat were conducted in female rats and rabbits. There were no effects on female rat fertility or rabbit embryo-fetal development. Administration of Ervogastat to pregnant rats during organogenesis reduced fetal weight and caused higher incidences of bent bones in fetuses that were shown to resolve by postnatal day 28 and were therefore considered to be transient variations secondary to developmental delay. Extended dosing in rats through the end of gestation and lactation (pre- and post-natal development study) caused impaired skin development, reduced offspring viability, and growth retardation. The spectrum of developmental effects in rats is consistent with the intended pharmacology (altered triglyceride metabolism) and the transient nature of the skeletal findings, along with the late gestational window of sensitivity for the effects on skin barrier development, reduce the concern for potential adverse developmental effects following unintended early gestational exposure to Ervogastat in humans where treatment can be discontinued once pregnancy is determined.
Inhibition of Diacylglycerol Acyltransferase 2 Versus Diacylglycerol Acyltransferase 1: Potential Therapeutic Implications of Pharmacology
Clin Ther 2023 Jan;45(1):55-70.PMID:36690550DOI:10.1016/j.clinthera.2022.12.008.
Purpose: Hepatic steatosis due to altered lipid metabolism and accumulation of hepatic triglycerides is a hallmark of nonalcoholic fatty liver disease (NAFLD). Diacylglycerol acyltransferase (DGAT) enzymes, DGAT1 and DGAT2, catalyze the terminal reaction in triglyceride synthesis, making them attractive targets for pharmacologic intervention. There is a common misconception that these enzymes are related; however, despite their similar names, DGAT1 and DGAT2 differ significantly on multiple levels. As we look ahead to future clinical studies of DGAT2 inhibitors in patients with NAFLD and nonalcoholic steatohepatitis (NASH), we review key differences and include evidence to highlight and support DGAT2 inhibitor (DGAT2i) pharmacology. Methods: Three Phase I, randomized, double-blind, placebo-controlled trials assessed the safety, tolerability, and pharmacokinetic properties of the DGAT2i Ervogastat (PF-06865571) in healthy adult participants (Single Dose Study to Assess the Safety, Tolerability and Pharmacokinetics of PF-06865571 [study C2541001] and Study to Assess the Safety, Tolerability, and Pharmacokinetics of Multiple Doses of PF-06865571 in Healthy, Including Overweight and Obese, Adult Subjects [study C2541002]) or participants with NAFLD (2-Week Study in People With Nonalcoholic Fatty Liver Disease [study C2541005]). Data from 2 Phase I, randomized, double-blind, placebo-controlled trials of the DGAT1i PF-04620110 in healthy participants (A Single Dose Study of PF-04620110 in Overweight and Obese, Otherwise Healthy Volunteers [study B0961001] and A Multiple Dose Study of PF-04620110 in Overweight and Obese, Otherwise Healthy Volunteers [study B0961002]) were included for comparison. Safety outcomes were the primary end point in all studies, except in study C2541005, in which safety was the secondary end point, with relative change from baseline in whole liver fat at day 15 assessed as the primary end point. Safety data were analyzed across studies by total daily dose of Ervogastat (5, 15, 50, 100, 150, 500, 600, 1000, and 1500 mg) or PF-04620110 (0.3, 1, 3, 5, 7, 10, 14, and 21 mg), with placebo data pooled separately across Ervogastat and PF-04620110 studies. Findings: Published data indicate that DGAT1 and DGAT2 differ in multiple dimensions, including gene family, subcellular localization, substrate preference, and specificity, with unrelated pharmacologic inhibition properties and differing safety profiles. Although initial nonclinical studies suggested a potentially attractive therapeutic profile with DGAT1 inhibition, genetic and pharmacologic data suggest otherwise, with common gastrointestinal adverse events, including nausea, vomiting, and diarrhea, limiting further clinical development. Conversely, DGAT2 inhibition, although initially not pursued as aggressively as a potential target for pharmacologic intervention, has consistent efficacy in nonclinical studies, with reduced triglyceride synthesis accompanied by reduced expression of genes essential for de novo lipogenesis. In addition, early clinical data indicate antisteatotic effects with DGAT2i Ervogastat, in participants with NAFLD, accompanied by a well-tolerated safety profile. Implications: Although pharmacologic DGAT1is are limited by an adverse safety profile, data support use of DGAT2i as an effective and well-tolerated therapeutic strategy for patients with NAFLD, NASH, and NASH with liver fibrosis. Clinicaltrials: gov identifiers: NCT03092232, NCT03230383, NCT03513588, NCT00799006, and NCT00959426.