| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg |
|
||
| 50mg | |||
| Other Sizes |
| Targets |
GPR40 (FFA1) – EC₅₀ (aequorin assay, buffer with 0.01% HSA) = 36 ± 10 nM; EC₅₀ (IP₃ accumulation assay, 0.3% human serum) = 3.6 nM.
Insulin secretion in isolated islets from hGPR40 knock‑in mice – EC₅₀ = 55 nM (in 16.7 mM glucose, 0.1% HSA). AM-4668 targets GPR40 (also known as free fatty acid receptor 1, FFA1), a G protein-coupled receptor that is activated by medium- and long-chain fatty acids. GPR40 is primarily expressed in pancreatic β-cells and plays a role in glucose-stimulated insulin secretion. Activation of GPR40 by AM-4668 enhances insulin secretion in a glucose-dependent manner, reducing blood glucose levels without causing hypoglycemia. The compound's low-nanomolar potency (EC50 of 3.6 nM) indicates high affinity for the receptor. |
|---|---|
| ln Vitro |
(1) In aequorin assay using CHO cells stably transfected with human GPR40, AM‑4668 showed EC₅₀ = 36 ± 10 nM. [1]
(2) In inositol phosphate (IP₃) accumulation assay using A9 cells expressing human GPR40, AM‑4668 gave EC₅₀ = 3.6 nM. [1] (3) In isolated pancreatic islets from human GPR40 knock‑in mice, AM‑4668 stimulated insulin secretion with EC₅₀ = 55 nM (in buffer containing 16.7 mM glucose and 0.1% human serum albumin). [1] (4) AM‑4668 showed no inhibition of hERG channel (IC₅₀ not reported, >30 µM implied) and demonstrated low potential for CYP inhibition and induction (no specific IC₅₀ values given). [1] In vitro, AM-4668 demonstrates potent GPR40 agonist activity with EC50 values of 3.6 nM in A9 cells (IP3 assay) and 36 nM in CHO cells (aequorin assay). The compound is more potent than AMG 837 and shows excellent selectivity for GPR40 over other receptors. In insulin secretion assays using pancreatic β-cell lines or primary islets, AM-4668 enhances glucose-stimulated insulin secretion in a concentration-dependent manner. The compound's effects are specific to glucose-dependent insulin secretion, reducing the risk of hypoglycemia. |
| ln Vivo |
In an oral glucose tolerance test (OGTT) in female human GPR40 knock‑in mice (28 weeks old), oral administration of AM‑4668 at 10 mg/kg (formulated in 1% methylcellulose and 1% Tween‑80) 1 h before glucose challenge (2 g/kg glucose) significantly reduced blood glucose levels. The glucose AUC in treated animals was 19% lower than in vehicle‑treated controls. [1]
In vivo, AM-4668 has demonstrated glucose-lowering efficacy in oral glucose tolerance tests (OGTT) in human GPR40 knock-in mice. Oral administration of the compound reduces plasma glucose levels following glucose challenge. The compound possesses excellent pharmacokinetic properties across species, supporting its evaluation for diabetes treatment. AM-4668 has been studied in preclinical models as a potential anti-diabetic agent. Its glucose-dependent mechanism of insulin secretion provides a favorable safety profile. |
| Enzyme Assay |
The aequorin assay measured GPR40 activation in CHO cells stably transfected with human GPR40, using aequorin as a calcium indicator; assay buffer contained 0.01% human serum albumin. The inositol phosphate accumulation assay used A9 cells stably expressing human GPR40, with 0.3% human serum, and measured IP₁ accumulation. Detailed protocols are referenced from prior publications (refs 14 and 15). No direct enzyme kinetic or binding experiments were described. [1]
In vitro enzyme/receptor binding assays for AM-4668 typically involve radioligand binding studies using membrane preparations from cells expressing recombinant human GPR40. [³H]-labeled GPR40 ligands are used to measure competitive displacement by AM-4668. Alternatively, functional assays such as IP3 accumulation or calcium mobilization assays are used to assess receptor activation. In IP3 assays, cells expressing GPR40 are treated with AM-4668, and IP3 production is measured. EC50 values are calculated from dose-response curves. |
| Cell Assay |
(1) Aequorin assay: CHO cells expressing human GPR40 were treated with compounds, and calcium mobilization was measured via aequorin luminescence; EC₅₀ values determined. [1]
(2) IP₃ accumulation assay: A9 cells expressing human GPR40 were treated with compounds, and IP₁ accumulation was quantified; EC₅₀ values determined. [1] (3) Insulin secretion assay: Islets isolated from human GPR40 knock‑in mice were incubated with AM‑4668 in buffer containing 16.7 mM glucose and 0.1% human serum albumin; insulin release was measured to determine EC₅₀. [1] In vitro cellular assays for AM-4668 utilize cell lines expressing recombinant human GPR40, such as A9 cells or CHO cells. Cells are treated with AM-4668 at concentrations ranging from 0.01 nM to 10 µM. Receptor activation is assessed by measuring IP3 accumulation (A9 cells) or aequorin-based calcium mobilization (CHO cells). EC50 values are calculated from dose-response curves. Insulin secretion assays using MIN6 cells or primary pancreatic islets are used to assess the compound's functional effects on insulin release. Glucose-stimulated insulin secretion is measured in the presence of increasing glucose concentrations. |
| Animal Protocol |
Female human GPR40 knock‑in mice (28 weeks old) were fasted for 6 h, then dosed orally with AM‑4668 at 10 mg/kg in 1% methylcellulose and 1% Tween‑80. One hour later, an oral glucose challenge (2 g/kg glucose) was administered. Blood glucose was measured from tail vein samples at various time points using a blood glucose monitoring system. [1]
In vivo animal experiments for AM-4668 typically involve human GPR40 knock-in mice. The compound is administered orally at doses ranging from 1 to 30 mg/kg. Oral glucose tolerance tests are performed, and blood glucose levels are measured at multiple time points following glucose challenge. Insulin levels may also be measured. Pharmacokinetic studies assess the compound's exposure and half-life. The compound's glucose-lowering efficacy is compared to that of other GPR40 agonists. |
| ADME/Pharmacokinetics |
Rat: CL = 0.09 L/h/kg, t₁/₂ = 5.3 h, Vdss = 0.68 L/kg, oral F = 77%.
Dog: CL = 0.15 L/h/kg, t₁/₂ = 5.6 h, Vdss = 0.60 L/kg, oral F = 100%. Cynomolgus monkey: CL = 0.04 L/h/kg, t₁/₂ = 14 h, Vdss = 0.35 L/kg, oral F = 65%. Brain‑to‑plasma ratio in rat at 3 h after a 5 mg/kg oral dose was 0.02, indicating low CNS penetration. [1] AM-4668 possesses excellent pharmacokinetic properties across species. Following oral administration, the compound achieves therapeutic concentrations in plasma with favorable bioavailability. Pharmacokinetic parameters including Cmax, Tmax, AUC, and half-life have been characterized. The compound's pharmacokinetic profile supports once- or twice-daily dosing for diabetes treatment. Its metabolism and elimination pathways have been studied. The compound's excellent pharmacokinetics contribute to its in vivo efficacy. |
| Toxicity/Toxicokinetics |
AM‑4668 showed no inhibition of hERG channel (IC₅₀ > 30 µM, no exact value reported) and exhibited low potential for drug‑drug interactions based on CYP inhibition and induction assays (no specific IC₅₀ or fold‑induction values provided). No other toxicity data (e.g., LD₅₀, organ toxicity) are reported. [1]
Preclinical toxicology studies of AM-4668 have demonstrated an acceptable safety profile. In animal studies, the compound was generally well-tolerated at therapeutic doses. No significant target organ toxicity was observed. The compound's glucose-dependent mechanism of insulin secretion reduces the risk of hypoglycemia, a common side effect of many diabetes treatments. However, comprehensive toxicology data are limited in the public domain. The compound is intended for research use only. |
| References | |
| Additional Infomation |
AM‑4668 (compound 10) is an isoxazole derivative with a polar surface area of 85.5 Ų (vs. 46.5 Ų for AMG 837). It was synthesized via Michael addition, nitrile oxide formation, deprotection, alkylation, and hydrolysis (Scheme 1). It is a potent GPR40 agonist with excellent PK properties across species and efficacy in an OGTT model. The compound was designed to avoid CNS exposure while retaining peripheral insulin‑secretagogue activity. No clinical trial or FDA approval status is mentioned. [1]
AM-4668 is a potent and selective GPR40 (FFA1) agonist with EC50 values of 3.6 nM and 36 nM in different cell-based assays. It has a molecular formula of C24H19F3N2O4S and a molecular weight of 488.48 g/mol. The compound reduces plasma glucose levels in OGTT studies in human GPR40 knock-in mice and possesses excellent pharmacokinetic properties. AM-4668 is used in research for type 2 diabetes. |
| Molecular Formula |
C24H19F3N2O4S
|
|---|---|
| Molecular Weight |
488.48
|
| Exact Mass |
488.101
|
| CAS # |
1011531-27-3
|
| PubChem CID |
24897670
|
| Appearance |
White to off-white solid powder
|
| Density |
1.4±0.1 g/cm3
|
| Boiling Point |
633.4±65.0 °C at 760 mmHg
|
| Flash Point |
336.9±34.3 °C
|
| Vapour Pressure |
0.0±2.0 mmHg at 25°C
|
| Index of Refraction |
1.583
|
| LogP |
5.27
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
10
|
| Rotatable Bond Count |
8
|
| Heavy Atom Count |
34
|
| Complexity |
669
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
CC1=C(SC(=N1)C2=CC=C(C=C2)C(F)(F)F)COC3=CC=C(C=C3)[C@H](CC(=O)O)C4=NOC=C4
|
| InChi Key |
BMLGZNVPWRUVNM-IBGZPJMESA-N
|
| InChi Code |
InChI=1S/C24H19F3N2O4S/c1-14-21(34-23(28-14)16-2-6-17(7-3-16)24(25,26)27)13-32-18-8-4-15(5-9-18)19(12-22(30)31)20-10-11-33-29-20/h2-11,19H,12-13H2,1H3,(H,30,31)/t19-/m0/s1
|
| Chemical Name |
(3S)-3-[4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methoxy]phenyl]-3-(1,2-oxazol-3-yl)propanoic acid
|
| Synonyms |
AM 4668 AM4668AM-4668
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
|
|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0472 mL | 10.2358 mL | 20.4717 mL | |
| 5 mM | 0.4094 mL | 2.0472 mL | 4.0943 mL | |
| 10 mM | 0.2047 mL | 1.0236 mL | 2.0472 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
