fasiglifam (TAK-875) / Takeda - LARVOL DELTA

Discovery of ZYDG2: a potent, selective, and safe GPR40 agonist for treatment of type 2 diabetes. (PubMed, J Pharmacol Exp Ther) - "This robust data conclusively demonstrates that ZYDG2 is a highly promising and unequivocally safe therapeutic candidate for the treatment of type 2 diabetes. SIGNIFICANCE STATEMENT: ZYDG2 is a potent, selective, and safe GPR40 agonist which may be a promising candidate for the treatment of type 2 diabetes as it has shown better efficacy and safety profile compared with fasiglifam."

Journal • Diabetes • Hepatology • Metabolic Disorders • Type 2 Diabetes Mellitus

Recent Developments in Drug Design of Oral Synthetic Free Fatty Acid Receptor 1 Agonists. (PubMed, Drug Des Devel Ther) - "Over the past two decades, synthetic FFAR1 agonists such as TAK-875 and TSL1806 have undergone meticulous design and extensive clinical trials...Recent studies have concentrated on developing low-molecular-weight compounds that more closely resemble natural products, with CPL207280 showing promising potential and liver safety, currently in Phase II clinical trials. Moreover, ongoing research continues to explore the potential applications of FFAR1 agonists in diabetes management, as well as in conditions such as non-alcoholic fatty liver disease (NAFLD) and cerebrovascular diseases. Utilizing advanced technologies such as artificial intelligence and computer-aided design, the development of compact molecules that mimic natural structures represents a hopeful direction for future research and development."

Journal • Review • CNS Disorders • Diabetes • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Vascular Neurology

Lower hepatotoxicity risk in Xelaglifam, a novel GPR40 agonist, compared to Fasiglifam for type 2 diabetes therapy. (PubMed, Biomed Pharmacother) - "Notably, toxicity studies in rats and monkeys showed no adverse liver effects at higher exposure levels than the effective human blood concentration. Overall, these results support a low risk of DILI for Xelaglifam treatment and the justification for its long-term use for treating type 2 diabetes."

Journal • Diabetes • Hepatology • Liver Failure • Metabolic Disorders • Type 2 Diabetes Mellitus

Enteroendocrine cell-derived peptide YY signalling is stimulated by pinolenic acid or Intralipid and involves coactivation of fatty acid receptors FFA1, FFA4 and GPR119. (PubMed, Neuropeptides) - "The agonists used were; FFA1, TAK-875 or AM-1638; for FFA4, Merck A; or for GPR119, AR231453, PSN632408 or AR440006...PA (EC50 = 298.2 nM) co-activated epithelial FFA1 and FFA4 and involved endogenous PYY Y1/Y2-receptor mechanisms but desensitisation was observed between PA and high GPR119 agonist concentrations. Apical Intralipid co-activated FFA1, FFA4 and GPR119 with a residual component not being attributable to PYY, or this trio of fatty acid receptors."

Journal

Xelaglifam, a novel GPR40/FFAR1 agonist, exhibits enhanced β-arrestin recruitment and sustained glycemic control for type 2 diabetes. (PubMed, Biomed Pharmacother) - "This study investigated the effects of Xelaglifam in comparison with Fasiglifam on the in vitro/in vivo anti-diabetic efficacy and selectivity, and the mechanistic basis...Co-treatment of Xelaglifam with SGLT-2 inhibitors showed additive or synergistic effects. Collectively, these results demonstrate the therapeutic efficacy and selectivity of Xelaglifam on GPR40, supportive of its potential for the treatment of Type 2 diabetes."

Journal • Diabetes • Hypoglycemia • Metabolic Disorders • Type 2 Diabetes Mellitus

The GPR40 novel agonist SZZ15-11 improves non-alcoholic fatty liver disease by activating the AMPK pathway and restores metabolic homeostasis in diet-induced obese mice. (PubMed, Diabetes Obes Metab) - "This study confirmed that SZZ15-11, a novel GPR40 agonist, improves hyperlipidaemia and fatty liver, partially via Gs signalling and the AMPK pathway in hepatocytes."

Journal • Preclinical • Diabetes • Dyslipidemia • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity

Repurposing TAK875 as a novel STAT3 inhibitor for treating inflammatory bowel disease. (PubMed, Biochem Pharmacol) - "Finally, we demonstrated its satisfactory anti-inflammatory effect in a dextran sulfate sodium-induced mouse model of ulcerative colitis. In conclusion, this study presented TAK875 as a novel STAT3 inhibitor and demonstrated its anti-inflammatory and antioxidant effects both in vitro and in vivo."

Journal • Colon Cancer • Colorectal Cancer • Gastroenterology • Gastrointestinal Cancer • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Oncology • Solid Tumor • Ulcerative Colitis • CD4

AM1638, a GPR40-Full Agonist, Inhibited Palmitate- Induced ROS Production and Endoplasmic Reticulum Stress, Enhancing HUVEC Viability in an NRF2-Dependent Manner. (PubMed, Endocrinol Metab (Seoul)) - "Those antioxidant effects were not detected after treatment with LY2922470 or TAK875, GPR40-partial agonists, suggesting that GPR40 regulates reactive oxygen species (ROS) removal in a ligand-dependent manner. In particular, AM1638 reduced palmitate-induced superoxide production and cytotoxicity in an NRF2/HO-1 dependent manner. GPR40 could be developed as a good therapeutic target to prevent or treat cardiovascular diseases such as atherosclerosis."

Journal • Atherosclerosis • Cardiovascular • Diabetes • Dyslipidemia • Metabolic Disorders • CASP3 • HMOX1 • XBP1

GPR40 agonist, an emerging antidiabetic agent, regulates foam cell formation and endothelial cytotoxicity (EASD 2023) - "Both LY2922470 and TAK875 significantly reduced palmitate mediated endoplasmic reticulum (ER) stress, caspase-3 and poly ADP-ribose polymerase (PARP) cleavage and lactate dehydrogenase (LDH) release. GPR40 has beneficial effects on metabolic stimuli in vascular endothelial cells and THP-1 cells. Since chronic and excessive inflammation and cytotoxicity are known to be responsible for foam cell formation, plaque development and plaque instability, GPR40 might represent a good therapeutic target to overcome cardiovascular diseases (CVD) such as atherosclerosis."

Diabetes • Metabolic Disorders • AMPK • CASP3 • CD36

Oral administration of linoleic acid immediately before glucose load ameliorates postprandial hyperglycemia. (PubMed, Front Pharmacol) - " Male rats and rats with type 1 diabetes administered streptozocin were orally administered LA, trilinolein, α-linolenic acid (α-LA), oleic acid, TAK-875, or TUG-891 immediately before glucose load. Oral administration of LA immediately after glucose load ameliorated postprandial hyperglycemia due to slowing of gastric emptying via promotion of GLP-1 secretion. The mechanisms may be associated with GPR120 pathway."

Journal • Diabetes • Metabolic Disorders • Type 1 Diabetes Mellitus

Molecular mechanism of fatty acid activation of FFAR1. (PubMed, Proc Natl Acad Sci U S A) - "We used cryo-electron microscopy to elucidate structures of activated FFAR1 bound to a G mimetic, which were induced either by the endogenous FFA ligand docosahexaenoic acid or γ-linolenic acid and the agonist drug TAK-875. Our data identify the orthosteric pocket for fatty acids and show how both endogenous hormones and synthetic agonists induce changes in helical packing along the outside of the receptor that propagate to exposure of the G-protein-coupling site. These structures show how FFAR1 functions without the highly conserved "DRY" and "NPXXY" motifs of class A GPCRs and also illustrate how the orthosteric site of a receptor can be bypassed by membrane-embedded drugs to confer full activation of G protein signaling."

Journal • Diabetes • Metabolic Disorders

Yiqi Huazhuo decoction increases insulin secretion in type 2 diabetic rats by regulating the pancreatic GPR40-IP3R-1 signaling pathway. (PubMed, Front Pharmacol) - " T2DM rats were randomized to the model, YD-lo (15 mg/kg/d YD, 10 weeks), YD-hi (30 mg/kg/d YD, 10 weeks), positive drug (TAK-875), and healthy control groups...The changes in protein expression were similar to mRNA. YD promotes insulin secretion from pancreatic islet β-cell in T2DM rats by regulating the GPR40-IP3R-1 pathway, thereby reducing blood glucose."

Journal • Preclinical • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Discovery of orally effective and safe GPR40 agonists by incorporating a chiral, rigid and polar sulfoxide into β-position to the carboxylic acid. (PubMed, Eur J Med Chem) - "Particularly, the withdrawal of TAK-875 from clinical trials phase III due to liver toxicity concern threw doubt over the long-term safety of targeting GPR40...As a result, the conformational constraint, polarity as well as chirality endowed by the sulfoxide significantly enhanced the efficacy, selectivity and ADMET properties of the novel (S)- 2-(phenylsulfinyl)acetic acid-based GPR40 agonists. The lead compounds (S)-4a and (S)-4s exhibited robust plasma glucose-lowering effects and insulinotropic action during an oral glucose tolerance test in C57/BL6 mice, excellent pharmacokinetic profile and little hepatobiliary transporter inhibition, marginal cell toxicities against human primary hepatocyte at 100 μM."

Journal • Diabetes • Hepatology • Metabolic Disorders • Type 2 Diabetes Mellitus

Modeling drug-induced liver injury and screening for anti-hepatofibrotic compounds using human PSC-derived organoids. (PubMed, Cell Regen) - "Phenotypic changes in HLOs after treatment with tool compounds such as acetaminophen, fialuridine, methotrexate, or TAK-875 showed high concordance with human clinical data in drug safety testings. SD208 and Imatinib were identified that can significantly suppress fibrogenesis induced by TGFβ, LPS, or methotrexate. Taken together, our studies demonstrated the potential applications of HLOs in drug safety testing and anti-fibrotic drug screening."

Journal • Fibrosis • Hepatology • Immunology • Liver Failure • TGFB1

Investigation of the Pharmacokinetics and Metabolic Fate of Fasiglifam (TAK-875) in Male and Female Rats Following Oral and Intravenous Administration. (PubMed, Xenobiotica) - "10-fold more drug-related material by this route.Fasiglifam was the principal drug-related compound in plasma, with 15 metabolites, including the acyl glucuronide, also detected. In addition to previously identified metabolites, a novel biotransformation, that produced a side-chain shortened metabolite via elimination of CH from the acetyl side chain was noted with implications for drug toxicity."

Journal • PK/PD data • Preclinical

A FFAR1 full agonist restores islet function in models of impaired glucose-stimulated insulin secretion and diabetic non-human primates. (PubMed, Front Endocrinol (Lausanne)) - "Fasiglifam, binds to site-1 and stimulates intra-cellular calcium release and improves glycemic control in diabetic patients...Together these data suggest a mechanism for FFAR1 where agonists have direct effects on islet hormone secretion that can overcome a dysfunctional T2D phenotype. These unique characteristics of FFAR1 site-3 agonists make them an appealing potential therapy to treat type-2 diabetes."

Journal • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Hepatology • Metabolic Disorders • Nephrology • Non-alcoholic Steatohepatitis • Renal Disease • Type 2 Diabetes Mellitus

Enhanced chromatographic efficiency obtained with vacuum jacketed columns facilitates the rapid UHPLC/MS/MS-based analysis of fasiglifam in rat plasma. (PubMed, Talanta) - "In addition, the increased resolution provided by the VJC system also improved the separation of fasiglifam from common matrix interferences such as co-extracted phospholipids thereby reducing the potential for matrix effects. The concatenation of these improvements suggests that the VJC approach may indeed provide a pathway to more sensitive, robust and high throughput drug bioanalysis, with particular advantages for drug discovery applications."

Journal • Preclinical

Learn from failures and stay hopeful to GPR40, a GPCR target with robust efficacy, for therapy of metabolic disorders. (PubMed, Front Pharmacol) - "The proof-of-concept of GPR40 for control of hyperglycemia was achieved by clinical trials of partial GPR40 agonist, TAK-875, demonstrating a robust decrease in HbA (-1.12%) after chronic treatment in T2D...Notwithstanding the multiple safety concerns on the development of small-molecule GPR40 agonists for T2D, some partial and AgoPAM GPR40 agonists are still under clinical development. Here we review the most recent progress of GPR40 agonists development and the possible mechanisms of the side effects in different organs, and discuss the possibility of developing novel strategies that retain the robust efficacy of GPR40 agonists for metabolic disorders while avoid toxicities caused by off-target and on-target mechanisms."

Journal • Review • Diabetes • Hepatology • Liver Failure • Metabolic Disorders • Type 2 Diabetes Mellitus

Discovery of a structurally novel, potent, and once-weekly free fatty acid receptor 1 agonist for the treatment of diabetes. (PubMed, Eur J Med Chem) - "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."

Journal • Diabetes • Metabolic Disorders • Pain • Type 2 Diabetes Mellitus

Design, synthesis, spectroscopic characterization, computational analysis, and in vitro α-amylase and α-glucosidase evaluation of 3-aminopyridin-2(1H)-one based novel monothiooxamides and 1,3,4-thiadiazoles. (PubMed, Org Biomol Chem) - "Compounds 7a and 8b showed higher binding affinities for selected target proteins compared to the known anti-diabetic drugs acarbose and TAK-875. Moreover, some compounds (6a-c, 7a-c, 8b,c) showed pronounced cytoprotective activity. Thus, the compounds 5-8(a-c) synthesized by us, both according to the results of computer calculations and in vitro biological screening, showed their potential antidiabetic activity and high prospects for further in-depth studies, including in vivo studies."

Journal • Preclinical • Diabetes • Metabolic Disorders

Inhibition of NLRP3 inflammasome by GPR40 agonists (EASL-ILC 2022) - "Pre-exposure of BMDM to TAK875 suppressed ATP-induced intracellular Ca2+ increase, which was reversed by thapsigargin, a sarco/ endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor. These findings provide an evidence that free fatty acidsensing GPR40 plays a key role in NLRP3 inflammasome pathway."

Addiction (Opioid and Alcohol) • Anesthesia • Hepatology • Hypoglycemia • Immunology • Inflammation • Non-alcoholic Steatohepatitis • IL18 • IL1B • NLRP3

In Vitro DILI Risk Assessment of IDG16177, a Potent and Selective GPR40 Agonist, for the Treatment of Type 2 Diabetes (ADA 2022) - "Fasiglifam induced a significant accumulation of GCA at 4 µM lower than the human Cmax of 10 µM, whereas IDG16177 showed no significant accumulation at 1 µM higher than the predicted human Cmax of 0.3 µM.IDG16177 did not have a significant effect in quantitative evaluation of the activity of various transcription factors, whereas treatment with 10 uM fasiglifam for 24 hours significantly increased the activities of peroxisome proliferator activating receptor (PPAR), activator protein 1 (AP-1) and nuclear respiratory factor 2 (NRF2), which were highly correlated with liver disease pathogenesis/progression. Interestingly, treatment with 10 μM IDG16177 for 48 h increased the activity of FXR, a master regulator of BA metabolism that inhibits BA absorption system and BA synthesis and promotes BA enterohepatic circulation, by 1.58-fold.These results show that IDG16177 has the advantage of having a low DILI potential compared to fasiglifam in addition to its..."

Late-breaking abstract • Preclinical • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

GPR40 Agonism Modulates Inflammatory Reactions in Vascular Endothelial Cells. (PubMed, Diabetes Metab J) - "LPS treatment induced expression of adhesion molecules vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) and attachment of THP-1 cells to HUVECs, which were all decreased by LY2922470 but not TAK875. Our results showed that ligand-dependent agonism of GPR40 is a promising therapeutic target for overcoming inflammatory reactions in the endothelium."

Journal • Cardiovascular • Immunology • Inflammation • ICAM1 • VCAM1

GPR40 agonist inhibits NLRP3 inflammasome activation via modulation of nuclear factor-κB and sarco/endoplasmic reticulum Ca-ATPase. (PubMed, Life Sci) - "Pre-exposure of BMDMs to TAK875 suppressed the ATP-induced intracellular Ca increase, which was reversed by thapsigargin, a sarco/endoplasmic reticulum Ca-ATPase inhibitor. Oral administration of mice with TAK875 suppressed the increase in serum IL-1β in mice treated with lipopolysaccharide/D-galactosamine in vivo. These findings indicate that the free fatty acid-sensing GPR40 plays a key role in the NLRP3 inflammasome pathway."

Journal • Addiction (Opioid and Alcohol) • Hepatology • Hypoglycemia • Immunology • Inflammation • Non-alcoholic Steatohepatitis • IL18 • IL1B • NLRP3

Vagal afferent CCK receptor activation is required for GLP-1- induced satiation. (PubMed, Diabetes Obes Metab) - "In vivo activation of the FFA1 receptor with orally administered TAK875 increased plasma CCK concentration and, consistent with the effect of exogenous CCK, we found that prior oral administration of TAK875 increased the eating inhibitory effect of peripherally administered GLP-1...We found that the combined anorectic effect of TAK875 and GLP-1 was significantly attenuated in the absence of CCK receptor expressing VANs. Taken together, our results indicate that endogenous CCK interacts with GLP-1 to promote satiation and that activation of the FFA1 receptor can initiate this interaction by stimulating the release of CCK."

Journal • Gastrointestinal Disorder