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Purity: = 99.57%
Tirzepatide (formerly known as LY3298176; trade name Mounjaro) is a first-in-class dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that has been approved by FDA in May 2022 for the treatment of type 2 diabetes. In individuals with poorly controlled type 2 diabetes, the effectiveness and safety of co-stimulation of the GLP-1 and GIP receptors with LY3298176 were compared with placebo or selective stimulation of GLP-1 receptors with dulaglutide. With a respectable safety and tolerability profile, the dual GIP and GLP-1 receptor agonist LY3298176 demonstrated a markedly superior efficacy in weight loss and glucose control when compared to dulaglutide. Combined GIP and GLP-1 receptor stimulation might offer a new therapeutic option in the treatment of type 2 diabetes. Tirzepatide (Mounjaro), an approved treatment for adults with Type 2 diabetes, was given FDA approval in May 2022. It's the first drug in a brand-new class. GLP-1 agonists are already on the market, such as semaglutide (Ozempic, Rybelsus). But it's the first agonist to bind both GIP and GLP-1 receptors. Tirzepatide also has anti-obesity effects and is being studies in several clinical trials for Overweight/Obesity.
| Targets |
GIP (glucose-dependent insulin nutritive polypeptide); GLP-1 (glucagon-like peptide-1) receptor
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|---|---|
| ln Vitro |
Tirzepatide (LY3298176) demonstrates noticeably higher efficacy than dulaglutide in terms of weight loss and glucose control[1]. Tirzepatide is an imbalanced agonist of the GIPR and GLP-1R and shows biased signaling at the GLP-1R.Tirzepatide differentially induces internalization of the GIPR versus the GLP-1R.[2]
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| ln Vivo |
Tirzepatide (LY3298176) has shown better efficacy than dulaglutide in terms of glycemic control and weight loss [1].With chronic administration to mice, LY3298176 potently decreased body weight and food intake; these effects were significantly greater than the effects of a GLP-1 receptor agonist. [3]
Tirzepatide significantly improved impaired glucose tolerance, fasting blood glucose level, and insulin level in diabetic rats. Then, tirzepatide dramatically alleviated spatial learning and memory impairment, inhibited Aβ accumulation, prevented structural damage, boosted the synthesis of synaptic proteins and increased dendritic spines formation in diabetic hippocampus. Furthermore, some aberrant changes in signal molecules concerning inflammation signaling pathways were normalized after tirzepatide treatment in diabetic rats. Finally, PI3K/Akt/GSK3β signaling pathway was restored by tirzepatide.[4] |
| Enzyme Assay |
Competition binding with human GLP-1(7-36)NH2, GIP(1-42), tirzepatide, and semaglutide was performed essentially as described for homologous competition except that the assay buffer was 1.0 mM MgCl2, 2.5 mM CaCl2, 0.003% w/v Tween-20, 0.1% w/v bacitracin in 25 mM HEPES, pH 7.4, final concentrations with one Complete EDTA free protease inhibitor tablet added per 50 mL of buffer. Using GraphPad Prism 7 software, Bmax values for [125I]GLP-1(7-36)NH2 or [125I]GIP(1-42) binding to GLP-1R and GIPR membranes were determined by nonlinear regression analysis using the amount bound versus the concentration of competing homologous peptide added. The Bmax was used to calculate the number of receptors per cell. For competing peptides, Ki values were determined by nonlinear regression analysis using the amount of [125I]GLP-1(7-36)NH2 or [125I]GIP(1-42) bound versus the concentration of peptide added.[2]
|
| Cell Assay |
HEK293 cells stably expressing HA-GIPR-EFGP or HA–GLP-1R–EFGP clones were plated into poly-D-lysine–coated 96-well microplates and cultured until cells reached 80%–90% confluency. On the day of assay, growth media was removed, and cells were rinsed once with prewarmed starvation media (growth media without serum or antibiotics, supplemented with 0.1% casein) and equilibrated with fresh media for 1 hour at 37°C, 5% CO2. Concentration response curves of GLP-1, GIP, and tirzepatide were prepared in prewarmed starvation media, added to cells for designated times, and incubated at 37°C. At the end of the study, media was removed, and cells were placed on ice and fixed with Prefer fixative (Anatech) for 10 minutes. Fixative was removed, and cells were washed in PBS and blocked with Odyssey blocking buffer (Licor) for 1 hour. Cells were incubated with anti-HA/DyLight800 antibody (1:700) (Rockland Immunochemicals, 600-445-384) for 1 hour followed by washes with PBS-T. Plates were scanned using a Licor Clx scanner with the 800 nm channel laser to capture fluorescence signal in each well. Data were normalized to maximum concentrations of GLP-1 or GIP (100%) and no ligand (0%) and analyzed by nonlinear regression (sigmoidal concentration-response) and plotted using GraphPad Prism 7 software.[2]
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| Animal Protocol |
High fat diet and streptozotocin injection-induced diabetic rats were injected intraperitoneally with Tirzepatide (1.35 mg/kg) once a week. The protective effects were assessed using the Morris water maze test, immunofluorescence, and Western blot analysis. Golgi staining was adopted for quantified dendritic spines.[4]
Male Sprague Dawley rats weighing between 180 and 200 g (aged 7–8 weeks) were raised in Specific Pathogen Free (SPF) conditions with a light/dark cycle of 12 h/12 h and temperature–humidity (22°C ± 1°C, 50% ± 10%) controlled. All procedures were approved by the Animal Care and Use Committee of Hubei University of Science and Technology, Xianning, China (IACUC Number: 2021-03-003). Animal care and handling were performed according to the Declaration of management of laboratory animals regarding the care and use of laboratory animals. After 2 weeks adaptation with normal diet, a total of 32 rats were fed with HF diet (67.5% standard laboratory rat chow, 20% sugar, 10% lard, 2% cholesterol and 0.5% bile salts), while 24 rats were raised by standard chow. According to our previous study, 35 mg/kg STZ was injected by intraperitoneal injection in the rats of HF diet group, whereas normal group were injected with citrate buffer only. After 2 weeks feeding, 31 rats with a fasting blood glucose levels reaching 11.0 mmol/L were randomly divided into two experimental groups as follows: diabetes mellitus group (DM), DM + Tirzepatide group (Tirzepatide, 1.35 mg/kg, once a week). At the same time, 24 rats of standard chow group were randomly divided into control group (Con) and Con + Tirzepatide group (Tirzepatide, 1.35 mg/kg, once a week). All drugs were prepared preserving more than 1 year under given conditions avoiding degradation. Oral glucose tolerance test (OGTT) was performed on the 13th week. Behavioral test was conducted before the sacrificed week. Fasting blood glucose and body weight were measured weekly until the sacrificed week. In the 15th week, all rats were sacrificed and collected samples which were executed follow-up experiments. A timeline of experimental procedure is presented in Figure 1A.[4] |
| References |
[1]. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet. 2018 Nov 17;392(10160):2180-2193.
[2]. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020 Sep 3; 5(17): e140532. [3]. 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. Mol Metab. 2018 Dec:18:3-14. [4]. Tirzepatide ameliorates spatial learning and memory impairment through modulation of aberrant insulin resistance and inflammation response in diabetic rats. Front Pharmacol. 2023 Aug 28;14:1146960. |
| Additional Infomation |
Tirzepatide is a 39-amino acid linear polypeptide which is conjugated to a C20 fatty diacid moiety via a linker connected to lysine-20. It is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 agonist used for the management of type 2 diabetes mellitus. It has a role as a glucagon-like peptide-1 receptor agonist, an anti-obesity agent, a hypoglycemic agent, a gastric inhibitory polypeptide receptor agonist and an incretin mimetic.
Mounjaro is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise- as monotherapy when metformin is considered inappropriate due to intolerance or contraindications- in addition to other medicinal products for the treatment of diabetes. For study results with respect to combinations, effects on glycaemic control and the populations studied, see sections 4. 4, 4. 5 and 5. 1. Effects During Pregnancy and Lactation Summary of Use during Lactation: No information is available on the clinical use of tirzepatide during breastfeeding. Because tirzepatide is a large peptide molecule with a molecular weight of 4814 daltons, the amount in milk is likely to be low and absorption is unlikely because it is probably partially destroyed in the infant's gastrointestinal tract. Until more data become available, tirzepatide should be used with caution during breastfeeding, especially while nursing a newborn or preterm infant. |
| Molecular Formula |
C225H348N48O68
|
|---|---|
| Molecular Weight |
4813.45147800446
|
| Exact Mass |
4810.52
|
| Elemental Analysis |
C, 56.14; H, 7.29; N, 13.97; O, 22.60
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| CAS # |
2023788-19-2
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| Related CAS # |
Tirzepatide hydrochloride; Tirzepatide TFA;13C,15N Tirzepatide;Tirzepatide TFA (LY3298176 TFA);Tirzepatide hydrochloride (LY3298176 hydrochloride)
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| PubChem CID |
163285897
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| Sequence |
Tyr-{Aib}-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-{Aib}-Leu-Asp-Lys-Ile-Ala-Gln-{C20 diacid-gamma-Glu-(AEEA)2-Lys}-Ala-Phe-Val-Gln-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
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| SequenceShortening |
Y-{Aib}-EGTFTSDYSI-{Aib}-LDKIAQ-{C20 diacid-gamma-Glu-(AEEA)2-Lys}-AFVQWLIAGGPSSGAPPPS-NH2;
or
YXEGTFTSDY SIXLDKIAQK AFVQWLIAGG PSSGAPPPS
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| Appearance |
White to off-white solid powder
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| LogP |
-6.8
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| tPSA |
1790Ų
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| SMILES |
CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCCNC(=O)COCCOCCNC(=O)COCCOCCNC(=O)CC[C@H](C(=O)O)NC(=O)CCCCCCCCCCCCCCCCCCC(=O)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)NCC(=O)NCC(=O)N4CCC[C@H]4C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N5CCC[C@H]5C(=O)N6CCC[C@H]6C(=O)N7CCC[C@H]7C(=O)N[C@@H](CO)C(=O)N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)C(C)(C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H](CC8=CC=C(C=C8)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC9=CC=CC=C9)NC(=O)[C@H]([C@@H](C)O)NC(=O)CNC(=O)[C@H](CCC(=O)O)NC(=O)C(C)(C)NC(=O)[C@H](CC1=CC=C(C=C1)O)N
|
| InChi Key |
BTSOGEDATSQOAF-SMAAHMJQSA-N
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| InChi Code |
InChI=1S/C225H348N48O68/c1-23-126(10)183(264-198(311)146(64-50-52-88-226)246-202(315)157(109-180(297)298)252-199(312)152(103-124(6)7)261-223(337)225(21,22)269-217(330)185(128(12)25-3)266-209(322)163(120-278)257-200(313)153(107-138-74-78-141(282)79-75-138)250-203(316)158(110-181(299)300)253-207(320)162(119-277)259-216(329)187(134(18)280)267-206(319)155(106-136-60-44-41-45-61-136)254-215(328)186(133(17)279)262-174(289)114-237-193(306)147(83-87-179(295)296)260-222(336)224(19,20)268-192(305)143(227)104-137-72-76-140(281)77-73-137)214(327)242-131(15)190(303)244-148(80-84-168(228)283)196(309)245-145(65-51-53-89-231-175(290)121-340-100-99-339-97-91-233-176(291)122-341-101-98-338-96-90-232-170(285)86-82-150(221(334)335)243-171(286)70-46-38-36-34-32-30-28-26-27-29-31-33-35-37-39-47-71-178(293)294)195(308)240-130(14)191(304)248-154(105-135-58-42-40-43-59-135)205(318)263-182(125(8)9)212(325)247-149(81-85-169(229)284)197(310)251-156(108-139-111-234-144-63-49-48-62-142(139)144)201(314)249-151(102-123(4)5)204(317)265-184(127(11)24-2)213(326)241-129(13)189(302)236-112-172(287)235-115-177(292)270-92-54-66-164(270)210(323)258-161(118-276)208(321)256-160(117-275)194(307)238-113-173(288)239-132(16)218(331)272-94-56-68-166(272)220(333)273-95-57-69-167(273)219(332)271-93-55-67-165(271)211(324)255-159(116-274)188(230)301/h40-45,48-49,58-63,72-79,111,123-134,143,145-167,182-187,234,274-282H,23-39,46-47,50-57,64-71,80-110,112-122,226-227H2,1-22H3,(H2,228,283)(H2,229,284)(H2,230,301)(H,231,290)(H,232,285)(H,233,291)(H,235,287)(H,236,302)(H,237,306)(H,238,307)(H,239,288)(H,240,308)(H,241,326)(H,242,327)(H,243,286)(H,244,303)(H,245,309)(H,246,315)(H,247,325)(H,248,304)(H,249,314)(H,250,316)(H,251,310)(H,252,312)(H,253,320)(H,254,328)(H,255,324)(H,256,321)(H,257,313)(H,258,323)(H,259,329)(H,260,336)(H,261,337)(H,262,289)(H,263,318)(H,264,311)(H,265,317)(H,266,322)(H,267,319)(H,268,305)(H,269,330)(H,293,294)(H,295,296)(H,297,298)(H,299,300)(H,334,335)/t126-,127-,128-,129-,130-,131-,132-,133+,134+,143-,145-,146-,147-,148-,149-,150+,151-,152-,153-,154-,155-,156-,157-,158-,159-,160-,161-,162-,163-,164-,165-,166-,167-,182-,183-,184-,185-,186-,187-/m0/s1
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| Chemical Name |
20-[[(1R)-4-[2-[2-[2-[2-[2-[2-[[(5S)-5-[[(2S)-5-amino-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-[[2-[[(2S)-2-[[2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-2-methylpropanoyl]amino]-4-carboxybutanoyl]amino]acetyl]amino]-3-hydroxybutanoyl]amino]-3-phenylpropanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxypropanoyl]amino]-3-methylpentanoyl]amino]-2-methylpropanoyl]amino]-4-methylpentanoyl]amino]-3-carboxypropanoyl]amino]hexanoyl]amino]-3-methylpentanoyl]amino]propanoyl]amino]-5-oxopentanoyl]amino]-6-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[2-[[2-[(2S)-2-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[(2S)-2-[(2S)-2-[(2S)-2-[[(2S)-1-amino-3-hydroxy-1-oxopropan-2-yl]carbamoyl]pyrrolidine-1-carbonyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-2-oxoethyl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopropan-2-yl]amino]-6-oxohexyl]amino]-2-oxoethoxy]ethoxy]ethylamino]-2-oxoethoxy]ethoxy]ethylamino]-1-carboxy-4-oxobutyl]amino]-20-oxoicosanoic acid
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| Synonyms |
LY-3298176; LY 3298176; tirzepatide; LY3298176; BG 121; BG121; BG-121
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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) |
DMSO: ~50 mg/mL (~10.4 mM)
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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.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.2078 mL | 1.0388 mL | 2.0775 mL | |
| 5 mM | 0.0416 mL | 0.2078 mL | 0.4155 mL | |
| 10 mM | 0.0208 mL | 0.1039 mL | 0.2078 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05691712 | Active Recruiting |
Drug: Tirzepatide Drug: Placebo |
Diabetes Type 2 Diabetes Mellitus |
Eli Lilly and Company | February 5, 2023 | Phase 3 |
| February 5, 2023 | Active Recruiting |
Drug: Tirzepatide Drug: Semaglutide |
Obesity Overweight |
Eli Lilly and Company | April 21, 2023 | Phase 3 |
| NCT04255433 | Active Recruiting |
Drug: Tirzepatide Drug: Dulaglutide |
Type 2 Diabetes Mellitus | Eli Lilly and Company | May 29, 2020 | Phase 3 |
| NCT05564039 | Active Recruiting |
Drug: Tirzepatide Drug: Dulaglutide |
Type 2 Diabetes | Eli Lilly and Company | November 30, 2022 | Phase 4 |
| NCT04184622 | Active Recruiting |
Drug: Tirzepatide Drug: Placebo |
Overweight Obesity |
Eli Lilly and Company | December 4, 2019 | Phase 3 |
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