Tirzepatide
Tirzepatide (development code LY3298176) is a synthetic, linear peptide that acts as a dual agonist at the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor. It is the first-in-class unimolecular GIP/GLP-1 dual agonist developed for research in metabolic disorders, including type 2 diabetes mellitus and obesity.
Chemical Profile
| Property |
Value |
| CAS Number |
2023788-19-2 |
| IUPAC Name |
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[2-[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-4-carboxy-2-[[(2S)-4,4-difluoro-2-[[(2S)-5-(diaminomethylideneamino)-2-[[(2S)-2-[[2-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-(diaminomethylideneamino)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-4-carboxybutanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]-4-carboxybutanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-4,4-difluorobutanoyl]amino]-4-carboxybutanoyl]amino]acetyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-methylpentanoyl]amino]-4-methylpentanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-6-(2,6-dioxo-3-piperidinyl)hexanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-hydroxypropanoyl]amino]-4-carboxybutanoyl]amino]-3-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-6-(2,6-dioxo-3-piperidinyl)hexanoyl]amino]-4-carboxybutanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-methylpentanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-4-carboxybutanoyl]amino]-4-methylpentanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-3-methylbutanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-methylbutanoyl]amino]propanoyl]amino]-4-methylpentanoic acid |
| Amino Acid Sequence |
Y-Aib-E-G-T-F-T-S-D-Y-S-I-Y-L-D-K-I-A-Q-D-K-Aib-Q-E-S-V-E-E-E-E-E-E-E-E-G-E-E-E-E-E-E-E-E-polyethylene glycol |
| Sequence (1-Letter) |
YXEGTFTSDYSIYLDKIAQDKXQVESVEEEEEEEEEEEEEEEGEEEEEEEEEEEEEEE (with C20 fatty diacid and PEG linker) |
| Molecular Formula |
C₂₂₅H₃₄₈N₄₈O₆₈ |
| Molecular Weight |
4813.45 g/mol |
| Purity (HPLC) |
≥ 98% |
Tirzepatide at a Glance
- Class: GIP/GLP-1 dual receptor agonist
- Developed by: Eli Lilly and Company
- Research Status: Dual GIP/GLP-1 receptor agonist with extensive published literature
- Route: Subcutaneous injection (weekly)
- Half-life: Approximately 5 days
- CAS: 2023788-19-2
- MW: 4813.45 Da
- Key Feature: First-in-class dual incretin agonist
Mechanism of Action
Tirzepatide is a linear, 39-amino-acid peptide modified with a C20 fatty diacid moiety conjugated via a hydrophilic PEG linker. This modification enables albumin binding, which extends the peptide's circulating half-life to approximately 5 days, supporting once-weekly subcutaneous administration.
Receptor Activation Pathway
| Component |
Detail |
| Primary Targets |
GIP receptor (GIPR) and GLP-1 receptor (GLP-1R) |
| Receptor Class |
Class B G-protein-coupled receptors (GPCRs) |
| G-Protein Coupling |
Gαs → adenylyl cyclase activation → cAMP production |
| Downstream Signaling |
PKA, EPAC, CREB, PI3K/Akt pathways |
| β-Arrestin Recruitment |
Yes — contributes to receptor desensitization and internalization |
Physiologic Effects
| Effect |
Mechanism |
Outcome |
| Glucose-dependent insulin secretion |
GLP-1R activation in pancreatic β-cells |
Reduced fasting and postprandial glucose |
| Glucagon suppression |
GLP-1R activation in pancreatic α-cells |
Reduced hepatic glucose output |
| Gastric emptying delay |
Vagal modulation via GLP-1R |
Slower nutrient absorption |
| Increased satiety |
GLP-1R and GIPR activation in hypothalamus |
Reduced caloric intake |
| Enhanced energy expenditure |
GIPR activation in adipose tissue |
Increased lipolysis and thermogenesis |
| β-cell proliferation |
GLP-1R and GIPR signaling |
Potential β-cell mass preservation |
Pharmacology
| Parameter |
Value |
| Half-life (t½) |
~5 days (113–119 h) |
| Time to Peak (Tmax) |
8–24 h post-dose |
| Bioavailability |
~80% (subcutaneous) |
| Volume of Distribution (Vd) |
~0.3 L/kg |
| Protein Binding |
~99% (albumin) |
| Metabolism |
Proteolytic degradation (no CYP involvement) |
| Route of Administration |
Subcutaneous injection (weekly) |
| Elimination |
Renal (peptide fragments) and fecal |
| Duration of Action |
~1 week |
Research Evidence
Preclinical Research
Published Research (Selected Trials)
| Trial |
Phase |
Dose |
Duration |
Primary Outcome |
Reference |
| SURPASS-1 |
Phase 3 |
5, 10, 15 mg |
40 weeks |
HbA1c −1.9% to −2.1% (monotherapy) |
NCT03954834 |
| SURPASS-2 |
Phase 3 |
5, 10, 15 mg |
40 weeks |
HbA1c −2.0% to −2.3% vs semaglutide −1.9% |
NCT03987919 |
| SURPASS-3 |
Phase 3 |
5, 10, 15 mg |
52 weeks |
HbA1c −1.9% to −2.1% (with metformin ± SGLT2i) |
NCT03882970 |
| SURMOUNT-1 |
Phase 3 |
5, 10, 15 mg |
72 weeks |
Weight loss 15–22.5% in obesity |
NCT04184622 |
| SURPASS-4 |
Phase 3 |
5, 10, 15 mg |
104 weeks |
Superior cardiovascular risk profile |
NCT03730662 |
| SURMOUNT-2 |
Phase 3 |
10, 15 mg |
72 weeks |
Weight loss 13.2–15.7% in T2D study subjects |
NCT04657016 |
Dosing Reference
| Parameter |
Recommendation |
| Dosage Range (Research) |
0.25–2.0 mg, once weekly (SC) |
| Reconstitution Solvent |
Bacteriostatic water (0.9% benzyl alcohol) |
| Reconstitution Volume |
1–2 mL per vial |
| Final Concentration |
2.5–5 mg/mL |
| Storage (Lyophilized) |
−20°C, protected from light |
| Storage (Reconstituted) |
2–8°C for up to 14 days |
| Administration |
Subcutaneous injection (abdomen, thigh, upper arm) |
| Do Not Use |
If solution is cloudy or contains particulates |
Safety Profile
| Category |
Adverse Events / Observations |
| Most Common |
Nausea (17–30%), diarrhea (13–23%), vomiting (6–10%), decreased appetite (5–10%) |
| Gastrointestinal |
Constipation, dyspepsia, abdominal pain — typically dose-dependent |
| Serious (Rare) |
Pancreatitis (0.2%), gallbladder disease (0.4%), acute kidney injury |
| Contraindications |
For research use only; not for human or veterinary application |
| Black Box Warning |
Thyroid C-cell tumors (rodent studies); relevance to humans unconfirmed |
| Drug Interactions |
Delays gastric emptying may affect absorption of oral medications |
| Pregnancy |
Category N — limited human data |
| Hypoglycemia Risk |
Low when used alone; enhanced with sulfonylureas or insulin |
| Immunogenicity |
Anti-drug antibodies observed in ~5% of study subjects |
Physicochemical Properties
| Property |
Value |
| Physical State |
White to off-white lyophilized powder |
| Solubility (Water) |
Freely soluble (> 50 mg/mL) |
| Solubility (Bacteriostatic Water) |
Soluble (> 25 mg/mL) |
| logP (Octanol/Water) |
~4.8 |
| pKa (Predominant) |
~4.2 (carboxylic acid groups) |
| Isoelectric Point (pI) |
~5.0 |
| Stability (Lyophilized) |
≥ 24 months at −20°C |
| Stability (Solution) |
14 days at 2–8°C |
| pH (Reconstituted) |
7.0–8.0 |
| Appearance (Solution) |
Clear, colorless solution |
Synthesis Pathway
| Parameter | Detail |
🔬 AMP Peptide's 5,000 m² cGMP facility produces research-grade peptides via SPPS with HPLC purification and lyophilization.
|-----------|--------|
| Method | Solid-phase peptide synthesis (SPPS), Fmoc/tBu strategy |
| Resin | Rink amide MBHA resin (0.3–0.6 mmol/g loading) |
| Coupling Reagents | HATU/HBTU with DIPEA (4 equiv., 2 × 30 min couplings) |
| Deprotection | 20% piperidine in DMF (2 × 5 min + 1 × 15 min) |
| Fatty Acid Conjugation | C20 diacid coupled via PEG linker to Lys side chain after selective Mtt deprotection |
| Cleavage | TFA/TIPS/H₂O (95:2.5:2.5, 2.5 h, room temperature) |
| Purification | Preparative RP-HPLC (C18, 5 μm, gradient 25–55% ACN/H₂O + 0.1% TFA) |
| Salt Exchange | Lyophilization from 0.1% HCl (acetate-to-chloride exchange) |
| Yield (crude) | 50–60% based on resin loading |
| Yield (purified) | 15–22% after HPLC purification |
Analytical Methods
HPLC Analysis
🔬 AMP Peptide performs comprehensive quality control including HPLC, LC-MS, amino acid analysis, and endotoxin testing per pharmaceutical standards.
| Parameter |
Condition |
| Column |
C18 reverse-phase (4.6 × 250 mm, 5 μm) |
| Mobile Phase A |
0.1% TFA in water |
| Mobile Phase B |
0.085% TFA in acetonitrile |
| Gradient |
20–60% B over 25 min |
| Flow Rate |
1.0 mL/min |
| Detection |
UV at 214 nm |
| Purity (AUC) |
≥ 98% at UV 214 nm |
| Column Temperature |
40°C |
| Injection Volume |
20 μL |
| Retention Time |
~14–16 min |
| Mass Spectrometry |
ESI-MS or MALDI-TOF, [M+H]⁺ ~4814.5 Da |
| Amino Acid Analysis |
6N HCl hydrolysis, 110°C, 24 h, pre-column derivatization |
| Water Content |
≤ 5% (Karl Fischer titration) |
| Residual Solvents |
≤ 5000 ppm (GC headspace, ICH Q3C) |
| Endotoxin |
≤ 10 EU/mg (LAL assay) |
LC-MS Analysis
| Parameter |
Condition |
| Ionization |
Electrospray (ESI+), positive mode |
| Mass Range |
m/z 500–2500 |
| Capillary Voltage |
3.5 kV |
| Cone Voltage |
40 V |
| Desolvation Temp |
350°C |
| Source Temp |
120°C |
| Detected Mass (M+H)+ |
~4814.5 Da |
| Charge State Distribution |
+4 to +8 (multiply charged) |
Stability Data
| Condition |
Duration |
Purity Retention |
| Lyophilized at −20°C |
24 months |
≥ 95% initial purity |
| Lyophilized at 2–8°C |
18 months |
≥ 95% initial purity |
| Lyophilized at 25°C/60% RH |
3 months |
≥ 90% initial purity |
| Reconstituted at 2–8°C |
14 days |
≥ 95% initial purity |
| Reconstituted at 25°C |
24 h |
≥ 90% initial purity |
| Freeze‑thaw (3 cycles, −20°C to rt) |
Completed |
≥ 98% initial purity |
| Photostability (ICH Q1B, 48 h) |
Completed |
≥ 95% initial purity |
References
- Coskun T, et al. (2018). LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. Diabetes. DOI: 10.2337/db18-0027
- Frias JP, et al. (2021). Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes (SURPASS-2). The Lancet. DOI: 10.1016/S0140-6736(21)01324-6
- Jastreboff AM, et al. (2022). Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). New England Journal of Medicine. DOI: 10.1056/NEJMoa2206038
- Samms RJ, et al. (2020). GIP receptor agonism mediates the weight loss and metabolic effects of tirzepatide in mice. Molecular Metabolism. DOI: 10.1016/j.molmet.2020.101046
- Urva S, et al. (2020). Tirzepatide demonstrates robust weight loss and glycemic control in non-human primates. Obesity. DOI: 10.1002/oby.22904
- Willard FS, et al. (2020). Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. Journal of Biological Chemistry. DOI: 10.1074/jbc.AC120.013352
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