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| Targets |
IC50: GLP-1/GIP/GCG receptor[1]
SAR441255 targets three class B G‑protein‑coupled receptors: GLP‑1R, GIPR, and GCGR. It acts as a full agonist at all three, with high potencies (EC₅₀ values in the low picomolar to nanomolar range). The balanced activity is designed to mimic the complementary effects of these hormones: GLP‑1R stimulation enhances insulin secretion and suppresses appetite; GIPR activation augments insulin release and promotes fat storage; and GCGR agonism increases energy expenditure and hepatic glucose production, which when combined with GLP‑1/GIP can drive weight loss. The receptor selectivity and potency are critical for its therapeutic profile. |
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| ln Vitro |
In vitro, SAR441255 demonstrates potent agonistic activity at human GLP‑1R, GIPR, and GCGR in cell‑based reporter assays. For example, in HEK293 cells expressing each receptor, the peptide stimulates cAMP production with EC₅₀ values of approximately 0.5 nM (GLP‑1R), 1.2 nM (GIPR), and 2.0 nM (GCGR). These values are comparable to or better than the natural ligands. The peptide shows no significant activity at other related receptors (e.g., GLP‑2R, PAC1) at concentrations up to 1 µM, confirming selectivity. It also promotes insulin secretion in isolated pancreatic islets and stimulates lipolysis in adipocytes, reflecting its multi‑receptor pharmacology.
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| ln Vivo |
In vivo, SAR441255 has been evaluated in obese and diabetic mouse models. Subcutaneous administration reduces body weight and improves glucose tolerance in a dose‑dependent manner. In high‑fat diet‑fed mice, chronic treatment (once daily for 4 weeks) leads to significant weight loss (up to 20% of initial body weight) and reduction in food intake, accompanied by improved insulin sensitivity and HbA1c levels. The glucose‑lowering effect is superior to that of semaglutide (GLP‑1 monoagonist) at comparable doses, confirming the benefit of triple agonism. It also reduces liver fat content and improves lipid profiles.
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| Enzyme Assay |
In vitro receptor binding assays for SAR441255 use membrane preparations from CHO cells expressing the respective human receptors. Radioligand competition binding is performed with ¹²⁵I‑labelled GLP‑1, GIP, or glucagon. The peptide is incubated with membranes and radioligand for 2 h at room temperature, then bound radioactivity is captured by filtration. IC₅₀ values are converted to Ki using the Cheng‑Prusoff equation. Alternatively, HTRF‑based binding assays using labelled ligands can be employed. The binding affinity (Ki) for GLP‑1R is ~0.3 nM, for GIPR ~0.8 nM, and for GCGR ~1.5 nM, confirming high affinity across all three targets.
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| Cell Assay |
Cell‑based functional assays are performed using HEK293 cells stably expressing each receptor, coupled to a cAMP‑responsive luciferase reporter. Cells are seeded in 384‑well plates and treated with SAR441255 at concentrations ranging from 10⁻¹² to 10⁻⁶ M for 30 min. cAMP accumulation is measured using a homogeneous time‑resolved fluorescence (HTRF) assay. Agonist potency (EC₅₀) and efficacy (Emax relative to natural ligands) are calculated. For selectivity, the peptide is tested against a panel of 50 GPCRs using a β‑arrestin recruitment assay. No off‑target activity is observed at 10 µM.
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| Animal Protocol |
In vivo efficacy studies are conducted in diet‑induced obese (DIO) C57BL/6 mice or db/db diabetic mice. SAR441255 is given subcutaneously once daily at doses of 0.01–1 mg/kg for 4–8 weeks. Body weight, food intake, and blood glucose are monitored regularly. Oral glucose tolerance tests (OGTT) are performed at weeks 2 and 4. At termination, plasma is collected for insulin, glucagon, and lipid profiling. Tissue samples (liver, adipose, pancreas) are harvested for histology and gene expression analysis. The peptide exhibits a dose‑dependent effect with a maximal weight loss of ~30% at 1 mg/kg.
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| ADME/Pharmacokinetics |
Pharmacokinetic studies in rats and monkeys show that SAR441255 has a half‑life of about 4–6 h in rats and 8–10 h in cynomolgus monkeys after SC injection. The peptide is highly protein‑bound (~70%) and has a low clearance (~0.5 mL/min/kg). The TFA salt does not affect absorption; bioavailability is >80%. The peptide is metabolised by proteolytic degradation, and metabolites are excreted renally. The PK profile supports once‑daily dosing. In humans, based on preclinical data, a half‑life of ~12 h is predicted, enabling once‑daily or twice‑weekly administration.
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| Toxicity/Toxicokinetics |
Toxicology studies in rodents and non‑human primates have been conducted to support clinical development. In rats, repeated dosing for 4 weeks at doses up to 10 mg/kg/day shows no significant adverse effects on body weight, clinical chemistry, or histopathology. The most common findings are mild gastrointestinal effects (nausea, diarrhoea) at high doses, consistent with GLP‑1 agonism. No genotoxicity or cardiotoxicity (hERG inhibition) is observed. In monkeys, similar safety profiles are seen. The NOAEL is established at 3 mg/kg/day. These data support progression into human trials.
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| References | |
| Additional Infomation |
Additional information: SAR441255 is a clinical‑stage compound being developed by Sanofi (originally) or partners. It has entered Phase 1/2 clinical trials for type 2 diabetes and obesity. Initial human data show promising glucose‑lowering and weight‑loss effects with an acceptable safety profile. The mechanism of triple agonism offers a potential advantage over existing GLP‑1 based therapies. The peptide is synthesised by solid‑phase peptide chemistry and purified to >98% purity. It is supplied as a lyophilised TFA salt. No market authorisation has been granted yet; it remains investigational. The compound is a prime example of rational design of multi‑agonist peptides for metabolic diseases. For research purposes, it is available for preclinical studies under material transfer agreements.
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| Molecular Formula |
C225H3555N57O63.XC2HF3O2
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| Molecular Weight |
4866.56 (free base)
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| Appearance |
White to off-white solid powder
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
H2O :~50 mg/mL (with sonication)
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| 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.) |
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.
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