Semaglutide
Semaglutide (development code NN9535, OG217SC for oral) is a synthetic, linear peptide analogue of human glucagon-like peptide-1 (GLP-1) with approximately 94% sequence homology. It acts as a selective, long-acting GLP-1 receptor agonist and is one of the most extensively studied incretin-based therapeutics for metabolic research, including type 2 diabetes mellitus and obesity.
Chemical Profile
| Property |
Value |
| CAS Number |
910463-68-2 |
| IUPAC Name |
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-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)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-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]-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]-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]-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-3-methylbutanoyl]amino]-5-(diaminomethylideneamino)pentanamide |
| Amino Acid Sequence |
H-Aib-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A-K-E-F-I-A-W-L-V-R-G-R-G-C18 diacid |
| Sequence (1-Letter) |
HXEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (with C18 fatty diacid at Lys26) |
| Molecular Formula |
C₁₈₇H₂₉₁N₄₅O₅₉ |
| Molecular Weight |
4113.58 g/mol |
| Purity (HPLC) |
≥ 98% |
Semaglutide at a Glance
- Class: Selective GLP-1 receptor agonist
- Developed by: Novo Nordisk
- Research Status: Widely studied GLP-1 receptor agonist with extensive published literature
- Route: Subcutaneous injection (weekly) or oral (daily)
- Half-life: Approximately 7 days (SC); ~1 week (oral)
- CAS: 910463-68-2
- MW: 4113.58 Da
- Key Feature: Most published GLP-1 receptor agonist in the research literature
Mechanism of Action
Semaglutide is a 31-amino-acid GLP-1 analogue with two amino acid substitutions compared to native GLP-1(7-37): Aib (α-aminoisobutyric acid) at position 8 for DPP-4 resistance, and Arg at position 34 (replacing Lys). A C18 fatty diacid chain attached to Lys26 enables albumin binding, extending the circulating half-life to approximately 7 days.
GLP-1 Receptor Activation Pathway
| Component |
Detail |
| Primary Target |
GLP-1 receptor (GLP-1R) |
| Receptor Class |
Class B G-protein-coupled receptor (GPCR) |
| G-Protein Coupling |
Gαs → adenylyl cyclase activation → cAMP production |
| Downstream Signaling |
PKA, EPAC2, CREB, PI3K/Akt, MAPK/ERK |
| β-Arrestin Recruitment |
Yes — modulates receptor desensitization |
Physiologic Effects
| Effect |
Mechanism |
Outcome |
| Glucose-dependent insulin secretion |
GLP-1R activation in pancreatic β-cells |
Improved glycemic control, HbA1c reduction |
| Glucagon suppression |
GLP-1R activation in α-cells |
Reduced hepatic gluconeogenesis |
| Delayed gastric emptying |
Vagal GLP-1R signaling |
Reduced postprandial glucose excursions |
| Appetite suppression |
GLP-1R in hypothalamus (arcuate nucleus) |
Reduced caloric intake, weight loss |
| β-cell protection |
Anti-apoptotic signaling via PKA/CREB |
Potential preservation of β-cell mass |
| Cardiovascular protection |
Direct myocardial GLP-1R effects |
Reduced MACE in cardiovascular outcome trials |
| Neuroprotection |
GLP-1R in CNS |
Emerging research in neurodegeneration |
Pharmacology
| Parameter |
Value |
| Half-life (t½) |
~7 days (165–168 h) — SC; ~1 week — oral |
| Time to Peak (Tmax) |
12–24 h post-dose (SC); 1–3 h (oral) |
| Bioavailability |
~89% (SC); ~1% (oral) |
| Volume of Distribution (Vd) |
~0.3 L/kg |
| Protein Binding |
~99% (albumin) |
| Metabolism |
Proteolytic degradation (no CYP involvement) |
| Route of Administration |
Subcutaneous (weekly) or oral (daily) |
| Elimination |
Renal (peptide fragments) and fecal |
| Duration of Action |
~1 week (SC) |
Research Evidence
Preclinical Research
Published Research (Selected Trials)
Dosing Reference
| Parameter |
Recommendation |
| Dosage Range (Research) |
0.25–2.4 mg, once weekly (SC) |
| Reconstitution Solvent |
Bacteriostatic water (0.9% benzyl alcohol) |
| Reconstitution Volume |
1–2 mL per vial |
| Final Concentration |
1–2.5 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 (20–44%), diarrhea (13–28%), vomiting (5–15%), constipation (7–12%) |
| Gastrointestinal |
Abdominal pain, dyspepsia, flatulence — dose-dependent tolerability |
| Serious (Rare) |
Pancreatitis (0.1–0.3%), gallbladder disease (0.5–1.5%), retinopathy complications |
| Cardiovascular |
Heart rate increase (2–4 bpm); reduced MACE in CVOT |
| Contraindications |
For research use only; not for human or veterinary application |
| Regulatory Note |
Thyroid C-cell findings observed in rodent studies |
| Drug Interactions |
Delayed gastric emptying may affect absorption of oral medications |
| Hypoglycemia Risk |
Low as monotherapy; increased with sulfonylureas/insulin |
| Immunogenicity |
Anti-drug antibodies in ~1–3% of study subjects |
| Pregnancy |
Not recommended; limited human data |
Physicochemical Properties
| Property |
Value |
| Physical State |
White to off-white lyophilized powder |
| Solubility (Water) |
Freely soluble (> 50 mg/mL) |
| Solubility (Bacteriostatic Water) |
Soluble (> 20 mg/mL) |
| logP (Octanol/Water) |
~4.5 |
| pKa (Predominant) |
~4.1 (carboxylic acid groups) |
| Isoelectric Point (pI) |
~4.8 |
| Stability (Lyophilized) |
≥ 36 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 | C18 diacid coupled to Lys26 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) | 55–65% based on resin loading |
| Yield (purified) | 18–25% 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 |
~13–15 min |
| Mass Spectrometry |
ESI-MS or MALDI-TOF, [M+H]⁺ ~4114.6 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)+ |
~4114.6 Da |
| Charge State Distribution |
+3 to +7 (multiply charged) |
Stability Data
| Condition |
Duration |
Purity Retention |
| Lyophilized at −20°C |
36 months |
≥ 95% initial purity |
| Lyophilized at 2–8°C |
24 months |
≥ 95% initial purity |
| Lyophilized at 25°C/60% RH |
6 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
- Marso SP, et al. (2016). Semaglutide and cardiovascular outcomes in patients with type 2 diabetes (SUSTAIN-6). New England Journal of Medicine. DOI: 10.1056/NEJMoa1607141
- Wilding JPH, et al. (2021). Once-weekly semaglutide in adults with overweight or obesity (STEP-1). New England Journal of Medicine. DOI: 10.1056/NEJMoa2032183
- Lau J, et al. (2015). Discovery of semaglutide, a once-weekly GLP-1 analogue. Journal of Medicinal Chemistry. DOI: 10.1021/acs.jmedchem.5b00726
- Secher A, et al. (2014). The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. Journal of Clinical Investigation. DOI: 10.1172/JCI72434
- Lincoff AM, et al. (2023). Semaglutide and cardiovascular outcomes in obesity (SELECT). New England Journal of Medicine. DOI: 10.1056/NEJMoa2307563
- Davies M, et al. (2021). Semaglutide 2.4 mg in type 2 diabetes and obesity (STEP-2). The Lancet. DOI: 10.1016/S0140-6736(21)02713-6
- Husain M, et al. (2019). Oral semaglutide and cardiovascular outcomes (PIONEER-6). New England Journal of Medicine. DOI: 10.1056/NEJMoa1913163
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