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HWL-088 Sale

目录号 : GC63010

HWL-088 是一种高效的,具有口服活性的游离脂肪酸受体 1 (FFA1/GPR40) 激动剂 (EC50 为 18.9 nM),并具有中等 PPARδ 活性 (EC50 为 570.9 nM)。HWL-088 改善葡萄糖和脂质代谢,并具有抗糖尿病作用。

HWL-088 Chemical Structure

Cas No.:2378617-96-8

规格 价格 库存 购买数量
10mM (in 1mL DMSO)
¥3,465.00
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5 mg
¥3,150.00
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10 mg
¥5,220.00
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25 mg
¥9,900.00
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50 mg
¥15,300.00
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100 mg
¥22,500.00
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产品文档

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产品描述

HWL-088 is a highly potent and orally active free fatty acid receptor 1 (FFA1/GPR40) agonist (EC50 of 18.9 nM) with moderate PPARδ activity (EC50 of 570.9 nM) . HWL-088 improves glucose and lipid metabolism, and has anti-diabetic effects[1][2].

HWL-088 (0.3 μM and 3μM) significantly increases insulin secretion fromMIN6 cells at 25 mM but not at 2 mM glucose. HWL-088 reveales a dose-dependent insulinotropic effect in the presence of 25-mM glucose[2].

HWL-088 (40 mg/kg; oral gavage; daily; for 30 days; ob/ob mice) treatment improves β-cell function by up-regulation of pancreas duodenum homeobox-1, reduces fat accumulation in adipose tissue and alleviated fatty liver in ob/ob mice. The effect of HWL-088 involves a reduction in hepatic lipogenesis and oxidative stress, increased lipoprotein lipolysis, glucose uptake, mitochondrial function and fatty acid β-oxidation[2].

[1]. Li Z, et al. Discovery of HWL-088: A highly potent FFA1/GPR40 agonist bearing a phenoxyacetic acid scaffold. Bioorg Chem. 2019 Nov;92:103209.
[2]. Yueming Chen, et al. HWL-088, a new potent free fatty acid receptor 1 (FFAR1) agonist, improves glucolipid metabolism and acts additively with metformin in ob/ob diabetic mice. Br J Pharmacol. 2020 May;177(10):2286-2302.

Chemical Properties

Cas No. 2378617-96-8 SDF
分子式 C22H19FO4 分子量 366.38
溶解度 DMSO : 250 mg/mL (682.35 mM; Need ultrasonic) 储存条件 Store at -20°C
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1 mM 2.7294 mL 13.647 mL 27.2941 mL
5 mM 0.5459 mL 2.7294 mL 5.4588 mL
10 mM 0.2729 mL 1.3647 mL 2.7294 mL
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Research Update

HWL-088, a new potent free fatty acid receptor 1 (FFAR1) agonist, improves glucolipid metabolism and acts additively with metformin in ob/ob diabetic mice

Br J Pharmacol 2020 May;177(10):2286-2302.PMID:31971610DOI:10.1111/bph.14980.

Background and purpose: The free fatty acid receptor 1 (FFAR1) plays an important role in glucose-stimulated insulin secretion making it an attractive anti-diabetic target. This study characterizes the pharmacological profile of HWL-088 (2-(2-fluoro-4-((2'-methyl-[1,1'- biphenyl]-3-yl)methoxy)phenoxy)acetic acid), a novel highly potent FFAR1 agonist in vitro and in vivo. Moreover, we investigated the long-term effects of HWL-088 alone and in combination with metformin in diabetic mice. Experimental approach: In vitro effects of HWL-088 on FFAR1 and PPARα/γ/δ were studied in cell-based assays. Glucose-dependent insulinotropic effects were evaluated in MIN6 cell line and in rats. Long-term effects on glucose and lipid metabolism were investigated in ob/ob mice. Key results: HWL-088 is a highly potent FFAR1 agonist (EC50 = 18.9 nM) with moderate PPARδ activity (EC50 = 570.9 nM) and promotes glucose-dependent insulin secretion in vitro and in vivo. Long-term administration of HWL-088 exhibited better glucose control and plasma lipid profiles than those of another FFAR1 agonist, TAK-875, and synergistic improvements were observed when combined with metformin. Moreover, HWL-088 and combination therapy improved β-cell function by up-regulation of pancreas duodenum homeobox-1, reduced fat accumulation in adipose tissue and alleviated fatty liver in ob/ob mice. The effect of HWL-088 involves a reduction in hepatic lipogenesis and oxidative stress, increased lipoprotein lipolysis, glucose uptake, mitochondrial function and fatty acid β-oxidation. Conclusion and implications: These data indicate that long-term treatment with HWL-088, a highly potent FFAR1 agonist, improves glucose and lipid metabolism and may be useful for the treatment of diabetes mellitus by mono-therapy or combination with metformin.

HWL-088, a new and highly effective FFA1/PPARδ dual agonist, attenuates nonalcoholic steatohepatitis by regulating lipid metabolism, inflammation and fibrosis

J Pharm Pharmacol 2020 Nov;72(11):1564-1573.PMID:32734608DOI:10.1111/jphp.13342.

Objectives: Nonalcoholic fatty liver (NAFLD), a chronic progressive liver disease, is highly correlated with pathoglycemia, dyslipidemia and oxidative stress. The free fatty acid receptor 1 (FFA1) agonists have been reported to improve liver steatosis and fibrosis, and the peroxisome proliferator-activated receptor δ (PPARδ) plays a synergistic role with FFA1 in energy metabolism and fibrosis. HWL-088, a PPARδ/FFA1 dual agonist, exerts better glucose-lowering effects than the representative FFA1 agonist TAK-875. However, the ability of HWL-088 to protect NAFLD was unknown. This study aimed to discover a new strategy for the treatment of NAFLD. Methods: The methionine- and choline-deficient diet (MCD)-induced Nonalcoholic steatohepatitis (NASH) model was constructed to evaluate the effects of HWL-088. Key findings: Administration of HWL-088 exerted multiple benefits on glucose control, lipid metabolism and fatty liver. Further mechanism research indicated that HWL-088 promotes lipid metabolism by decreasing lipogenesis and increasing lipolysis. Moreover, HWL-088 attenuates NASH by regulating the expression levels of genes related to inflammation, fibrosis and oxidative stress. Conclusions: These positive results indicated that PPARδ/FFA1 dual agonist HWL-088 might be a potential candidate to improve multiple pathogenesis of NASH.

Discovery of HWL-088: A highly potent FFA1/GPR40 agonist bearing a phenoxyacetic acid scaffold

Bioorg Chem 2019 Nov;92:103209.PMID:31487621DOI:10.1016/j.bioorg.2019.103209.

Based on a previously reported phenoxyacetic acid scaffold, compound 7 (HWL-088) has been identified as a superior free fatty acid receptor 1 (FFA1) agonist by comprehensive structure-activity relationship study. Our results indicated that the introduction of ortho-fluoro greatly increased the activity of phenoxyacetic acid series, and the unique structure-activity relationship in biphenyl moiety is different from previously reported FFA1 agonists. Moreover, the modeling study was also performed to better understand the binding mode of present series. Compound 7 significantly improved glucose tolerance both in normal and diabetic models, and even exerted greater potential on glucose control than that of TAK-875. These findings provided a novel candidate HWL-088, which is currently in preclinical study to evaluate its potential for the treatment of diabetes.

Discovery of a structurally novel, potent, and once-weekly free fatty acid receptor 1 agonist for the treatment of diabetes

Eur J Med Chem 2023 Jan 5;245(Pt 1):114883.PMID:36343410DOI:10.1016/j.ejmech.2022.114883.

Type 2 diabetes mellitus (T2DM) is a lifelong disease that requires long-term medication to control glucose levels, and thereby long-acting drug has been clinically needed for improving medical adherence. The free fatty acid receptor 1 (FFA1) was considered as a promising target for several diseases, such as T2DM, pain and fatty liver. However, no once-weekly FFA1 agonist has been reported until now. Herein, we report the successful discovery of ZLY50, the first once-weekly FFA1 agonist with a completely new chemotype, highly agonistic activity and selectivity on FFA1. Moreover, ZLY50 has enough brain exposure to activate FFA1 in brain, and it is the first orally available FFA1 agonist with analgesic activity. Notably, the long-term anti-diabetic and anti-fatty liver effects of ZLY50 (once-weekly) were better than those of HWL-088 (once-daily), a highly potent FFA1 agonist with far stronger glucose-lowering effect than Phase 3 clinical candidate TAK-875. Further mechanism studies suggested that ZLY50 alleviates fatty liver by regulating the expressions of genes related to lipid metabolism, mitochondrial function, and oxidative stress in liver.