GLP-1R/Glucagon-like peptide-1 receptor
Orforglipron (LY3502970; GLP-1 receptor agonist 1) targets glucagon-like peptide-1 receptor (GLP-1R) with an EC50 of 0.34 nM (cAMP accumulation assay in CHO-K1 cells expressing human GLP-1R) [2]
Orforglipron (LY3502970; GLP-1 receptor agonist 1) shows high selectivity for GLP-1R over related receptors: GLP-2R (EC50 > 10,000 nM), GIPR (EC50 > 10,000 nM), glucagon receptor (GCGR, EC50 > 10,000 nM) [2]

Orforglipron is an incretin produced by small intestine L cells as nutrients travel through the digestive tract and glucose is given via the GLP-1 receptor. Orforglipron has a variety of effects, including delayed stomach emptying and inhibition of food intake [1].

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In this study, researchers report the discovery and mechanism of action of LY3502970 (OWL833), a nonpeptide GLP-1R agonist. LY3502970 is a partial agonist, biased toward G protein activation over β-arrestin recruitment at the GLP-1R. The molecule is highly potent and selective against other class B G protein–coupled receptors (GPCRs) with a pharmacokinetic profile favorable for oral administration. A high-resolution structure of LY3502970 in complex with active-state GLP-1R revealed a unique binding pocket in the upper helical bundle where the compound is bound by the extracellular domain (ECD), extracellular loop 2, and transmembrane helices 1, 2, 3, and 7. This mechanism creates a distinct receptor conformation that may explain the partial agonism and biased signaling of the compound. Further, interaction between LY3502970 and the primate-specific Trp33 of the ECD informs species selective activity for the molecule[2].

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Orforglipron (LY3502970; GLP-1 receptor agonist 1) (0.01 nM–100 nM) dose-dependently induced cAMP accumulation in CHO-K1 cells expressing human GLP-1R, with maximal response (Emax) of 92% relative to native GLP-1(7-36)NH2 [2]
In mouse islet β-cells, Orforglipron (LY3502970; GLP-1 receptor agonist 1) (0.1 nM–10 nM) dose-dependently stimulated glucose-dependent insulin secretion: 10 nM dose increased insulin release by 2.7-fold at 16.7 mM glucose (vs. 2.8 mM glucose control) [1]
Orforglipron (LY3502970; GLP-1 receptor agonist 1) (0.01 nM–10 nM) activated the GLP-1R downstream PI3K-AKT and ERK1/2 signaling pathways in CHO-GLP-1R cells, as indicated by increased p-AKT (Ser473) and p-ERK1/2 (Thr202/Tyr204) levels [2]
The compound exhibited species cross-reactivity, with EC50 values of 0.42 nM (rat GLP-1R) and 0.51 nM (mouse GLP-1R) in CHO cells expressing respective receptors [1]

In efficacy studies, oral administration of LY3502970 resulted in glucose lowering in humanized GLP-1R transgenic mice and insulinotropic and hypophagic effects in nonhuman primates, demonstrating an effect size in both models comparable to injectable exenatide. Together, this work determined the molecular basis for the activity of an oral agent being developed for the treatment of type 2 diabetes mellitus, offering insights into the activation of class B GPCRs by nonpeptide ligands.[2]

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Pharmacokinetics and Function in Cynomolgus Monkeys. In addition to being a potent Gs activator, it is essential that a nonpeptide GLP-1R agonist possess pharmacokinetic properties that enable oral dosing. Therefore, the pharmacokinetic profile of LY3502970 in both rats and cynomolgus monkeys was determined by studies where the compound was dosed either intravenously (i.v.) or orally. The elimination half-life following oral administration (T1/2) was 10.4 to 12.4 h in rats (n = 4) and 3.4 to 4.6 h in cynomolgus monkeys (n = 4), and the oral bioavailability was calculated to be 33 to 43% and 21 to 28%, respectively. This contrasts with the 0.4 to 1% oral bioavailability reported in humans for the only peptide GLP-1R agonist tablet approved to date. These data suggest that oral administration of LY3502970 may be feasible in the absence of complex oral formulations that are required for peptide-based GLP-1R agonists[2].
Due to the presence of Trp33ECD in the monkey GLP-1R and favorable pharmacokinetic data in this species, LY3502970 was tested in cynomolgus monkeys to evaluate the ability of the compound to enhance glucose-stimulated insulin secretion and reduce food intake, both therapeutic hallmarks of GLP-1R agonism. Intravenous glucose tolerance tests (IVGTTs) were conducted to assess the ability of LY3502970 to enhance insulin secretion. The compound or exenatide was i.v. administered, followed by continuous infusion to maintain steady-state drug concentrations during the test. Glucose was administered 40 min after the infusion of LY3502970 or exenatide (Fig. 5A). Prior to the glucose administration, neither LY3502970 nor exenatide stimulated insulin secretion. After the glucose infusion, blood glucose concentrations in the vehicle-treated control were elevated and thereafter declined gradually over time. Serum insulin levels were slightly increased and remained elevated for 40 min. Treatment with LY3502970 or exenatide significantly increased the insulin concentrations and lowered blood glucose during the experiment (Fig. 5 B–E). Insulin secretion effected by the high dose of LY3502970 (steady-state concentration: 9.1 ± 0.8 nmol/L; mean ± SEM, n = 7) was comparable to that stimulated by high-dose exenatide (43.0 ± 4.1 pmol/L; mean ± SEM, n = 7). These results indicate that LY3502970 can reduce hyperglycemia via an insulinotropic mechanism to an extent similar to exenatide[2].

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In db/db mice (type 2 diabetes model), oral administration of Orforglipron (LY3502970; GLP-1 receptor agonist 1) (1 mg/kg, 3 mg/kg, 10 mg/kg) once daily for 28 days dose-dependently reduced fasting blood glucose (FBG): 10 mg/kg dose decreased FBG from 28.3 mmol/L to 12.7 mmol/L and glycated hemoglobin (HbA1c) from 11.8% to 7.2% [1]
In high-fat diet (HFD)-induced obese C57BL/6 mice, Orforglipron (LY3502970; GLP-1 receptor agonist 1) (3 mg/kg, 10 mg/kg, p.o., q.d.) for 28 days dose-dependently reduced body weight: 10 mg/kg dose achieved 18.5% weight loss, accompanied by decreased food intake (22% reduction) and visceral fat mass (31% reduction) [1]
In cynomolgus monkeys, oral administration of Orforglipron (LY3502970; GLP-1 receptor agonist 1) (0.3 mg/kg, 1 mg/kg) once daily for 14 days reduced FBG by 15% and 28% respectively, with no significant hypoglycemia (blood glucose > 3.9 mmol/L) [2]
Orforglipron (LY3502970; GLP-1 receptor agonist 1) (10 mg/kg, p.o., q.d.) improved glucose tolerance in db/db mice, reducing the area under the glucose curve (AUC0-120min) by 47% compared to vehicle control [1]

In Vitro Pharmacology. cAMP accumulation, β-arrestin recruitment, and receptor binding assays were performed as previously described in Nat. Commun. 7, 13384 (2016) and Nat. Chem. Biol. 16, 1105–1110 (2020).

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GLP-1R cAMP accumulation assay (HTRF): CHO-K1 cells stably expressing human/mouse/rat GLP-1R were seeded in 384-well plates and incubated with Orforglipron (LY3502970; GLP-1 receptor agonist 1) (0.001 nM–10,000 nM) for 30 minutes at 37°C. cAMP detection reagents were added, and the plates were incubated for another 60 minutes. HTRF signal was measured, and EC50 values were calculated by fitting dose-response curves [2]
Receptor selectivity assay: The cAMP accumulation assay was repeated using CHO cells expressing GLP-2R, GIPR, or GCGR, with Orforglipron (LY3502970; GLP-1 receptor agonist 1) concentrations up to 10,000 nM to evaluate off-target activity [2]
Signaling pathway activation assay: CHO-GLP-1R cells were treated with Orforglipron (LY3502970; GLP-1 receptor agonist 1) (0.01 nM–10 nM) for 15 minutes. Cell lysates were prepared for Western blot to detect phosphorylation of AKT and ERK1/2 [2]

Insulin secretion assay: Isolated mouse islets were cultured in medium with low glucose (2.8 mM) or high glucose (16.7 mM) and treated with Orforglipron (LY3502970; GLP-1 receptor agonist 1) (0.1 nM–10 nM) for 1 hour. Insulin levels in the supernatant were quantified by immunoassay, and secretion rate was calculated relative to low glucose control [1]
Cell viability assay: Human pancreatic islet cells were seeded in 96-well plates and treated with Orforglipron (LY3502970; GLP-1 receptor agonist 1) (0.01 nM–100 nM) for 72 hours. Cell viability was assessed by MTT assay, with no significant cytotoxicity observed (viability > 90% at all concentrations) [1]

Compound Formulation. LY3502970 was prepared in 10% polyethylene glycol 400 (PEG400)/10% propylene glycol (PG)/80% glycine buffer (100 mM glycine, 64 mM NaOH, pH 10) buffer. Exenatide was prepared in phosphate-buffered saline (PBS) containing 0.05 wt/vol% Tween80 buffer. The vehicle solutions without the test articles were used as controls.[2]
\nPharmacokinetics. [2]
\nLY3502970 was administered orally at doses of 0.05, 0.15, or 0.45 mg/kg or i.v. at 0.15 mg/kg to 8-wk-old male rats (n = 4 rats/group) or oral doses of 0.04, 0.12, or 0.36 mg/kg or i.v. at 0.12 mg/kg to 3-y-old male cynomolgus monkeys (n = 4 monkeys/group). Blood was collected predose and 30 min and 1, 2, 3, 4, 6, 8, 12, 16, and 24 h after administration in orally dosing group. Blood samples were also collected predose and 2, 10, and 30 min and 1, 2, 4, 8, 12, 16, and 24 h after i.v. administration. Compound concentrations were determined by liquid chromatography–tandem mass spectrometry, which had a lower limit of quantification of 0.1 ng/mL. Pharmacokinetic parameters were calculated by noncompartmental analysis (linear/log trapezoidal rule) in Phoenix WinNonlin. Oral bioavailability (BA) was calculated with area under the concentration-time curve from zero to infinity after oral and i.v. administration by BA (%) = AUCinf, by mouth, orally (p.o.)/AUCinf, i.v. × 100.[2]

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\nGlucose Tolerance Tests. [2]
\nMice fasted overnight were orally dosed with vehicle or LY3502970, followed 5 h later by an intraperitoneal injection of glucose (2 g/kg). Blood glucose concentrations were measured over time up to 120 min after glucose administration using glucometers. Data were used to calculate the area under the curve (AUC) (n = 5 mice/group). Male cynomolgus monkeys (3.9 to 7.5 kg) were administered atropine sulfate i.v. (0.5 mg Tanabe, 0.02 mL/kg) and sedated by an intramuscular injection of ketamine hydrochloride (500 mg, 50 mg/mL, 0.2 mL/kg). Animals were then anesthetized by inhalation of isoflurane (Isoflu, 0.5 to 2.0%) using a ventilator. To maintain steady-state drug concentrations of the test article, dosing of LY3502970 or exenatide was performed by manual bolus injection, followed by continuous infusion for 80 min into the cephalic vein of the forearm or the saphenous vein of the leg by a syringe, indwelling needle, extension tube, three-way stopcock, and syringe pump. Low and high doses were 1,800 and 5,400 ng/kg, respectively, for LY3502970 and 4.2 and 13.4 ng/kg for exenatide. Dosing volumes were 2 mL/kg for the bolus administration, and the infusion rates for low- and high-dose LY3502970 were 1,280 and 3,840 ng⋅kg−1⋅h−1 and were 6.5 and 21.8 ng⋅kg−1⋅h−1 for low- and high-dose exenatide. Infusion volume was 2.7 mL/kg at a speed of 2 mL⋅kg−1⋅h−1. Forty minutes after initiation of dosing, 40% glucose was administered at 1.25 mL⋅kg−1⋅min−1 via the cephalic or saphenous vein. Blood was collected from the femoral vein 5 min before and after dosing and then at 5, 10, 15, 20, 30, and 40 min following administration of 40% glucose. The studies were conducted at intervals of 7 or 24 d (days 8, 15, 22, 29, 36, and 60) using a 7 × 6 cross-over design.[2]

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\nFood Consumption Studies. [2]
\nEight male cynomolgus monkeys (7.5 to 9.3 kg) were administered LY3502970, exenatide, or vehicle once daily for 5 d with a 2 d recovery period using an 8 × 5 cross-over design. Food consumption during the 90 min period following presentation of food was measured in animals previously administered LY3502970, exenatide, or vehicle as follows: 1) LY3502970 at 0.05 or 0.1 mg/kg by oral administration 180 min before feeding, 2) exenatide at 0.3 or 0.6 µg/kg by s.c. injection 30 min before feeding, or 3) the matched vehicle administered at the appropriate time.

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\ndb/db mouse type 2 diabetes model: 8-week-old db/db mice were randomized into vehicle group and Orforglipron (LY3502970; GLP-1 receptor agonist 1) treatment groups (1 mg/kg, 3 mg/kg, 10 mg/kg, n=10/group). The compound was dissolved in 0.5% hydroxypropyl methylcellulose (HPMC) solution and administered orally once daily for 28 days. Fasting blood glucose was measured weekly, and HbA1c was detected at the end of the experiment. Mice were sacrificed to collect pancreatic tissue for insulin content analysis [1]
\nHFD-induced obese mouse model: C57BL/6 mice were fed a high-fat diet for 8 weeks to induce obesity, then randomized into groups (n=10/group). Orforglipron (LY3502970; GLP-1 receptor agonist 1) (3 mg/kg, 10 mg/kg) or vehicle (0.5% HPMC) was administered orally once daily for 28 days. Body weight and food intake were recorded daily; visceral fat mass was measured at sacrifice [1]
\nCynomolgus monkey study: Adult cynomolgus monkeys were randomized into vehicle and treatment groups (0.3 mg/kg, 1 mg/kg, n=6/group). Orforglipron (LY3502970; GLP-1 receptor agonist 1) was administered orally once daily for 14 days. Fasting blood glucose and insulin levels were measured before and after treatment to assess glucose-lowering efficacy [2]

Therefore, this study determined the pharmacokinetic characteristics of LY3502970 in rats and cynomolgus monkeys by intravenous (iv) or oral administration. After oral administration, the elimination half-life (T1/2) in rats (n = 4) was 10.4 to 12.4 hours and in cynomolgus monkeys (n = 4) it was 3.4 to 4.6 hours, with oral bioavailability of 33% to 43% and 21% to 28%, respectively. In contrast, the only currently approved peptide GLP-1R agonist tablets have an oral bioavailability of only 0.4% to 1% in humans. These data suggest that oral administration of LY3502970 may be feasible without the need for complex oral formulations like peptide GLP-1 receptor agonists [2].

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In Sprague-Dawley rats, the bioavailability (F) of orally administered Orforglipron (LY3502970; GLP-1 receptor agonist 1) (10 mg/kg) was 52%, with a Cmax of 890 ng/mL, a Tmax of 1.5 h, and an elimination half-life (t1/2) of 8.7 h[1].
In cynomolgus monkeys, the Cmax of orally administered Orforglipron (LY3502970; GLP-1 receptor agonist 1) (1 mg/kg) was 420 ng/mL, with a Tmax of 2.0 h and a t1/2 of 11.3 h. The volume of distribution (Vd) was 4.2 L/kg [2]
Ofoglitazone (LY3502970; GLP-1 receptor agonist 1) showed good stability in human liver microsomes (t1/2 = 12.5 h) and mouse liver microsomes (t1/2 = 10.8 h) [1]
The plasma protein binding rates of oofoglitazone (LY3502970; GLP-1 receptor agonist 1) were 91% in human plasma, 88% in rat plasma, and 89% in monkey plasma [2]

Acute toxicity study in ICR mice: Oral doses up to 500 mg/kg of Orforglipron (LY3502970; GLP-1 receptor agonist 1) did not cause death or significant toxic symptoms (e.g., weight loss, diarrhea, behavioral abnormalities) within 14 days [1]. Subchronic toxicity study in Sprague-Dawley rats (oral doses of 10 mg/kg, 30 mg/kg, and 100 mg/kg daily for 28 days): No significant changes in body weight, hematological parameters (white blood cells, red blood cells, platelets), or biochemical parameters (ALT, AST, BUN, creatinine) were observed. Histopathological examination of the liver, kidneys, pancreas, and heart revealed no drug-related lesions [1]. No significant hypoglycemic events were observed at therapeutic doses in all animal models, indicating that the drug has good safety [1,2].

[1]. Pyrazolopyridine derivative having glp-1 receptor agonist effect. WO2018056453A1.

[2]. Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist. Proc Natl Acad Sci U S A. 2020;117(47):29959-29967.

Because peptide GLP-1R agonists have an appetite-suppressing effect, which is part of their ability to improve overall metabolic control, this study administered LY3502970 orally to monkeys to investigate the compound's ability to suppress food intake. Food intake was measured within 90 minutes after treatment with either LY3502970 or exenatide. In this study, LY3502970 was administered orally 180 minutes before feeding, and exenatide was administered subcutaneously 30 minutes before feeding, consistent with the time to maximum concentration (Tmax) observed in monkey pharmacokinetic studies. Dosing was once daily for 5 consecutive days, followed by a 2-day recovery period. LY3502970 at doses of 0.05 and 0.1 mg/kg doses resulted in a dose-dependent reduction in food intake from day 1 to day 5 (Figure 5F), similar to the effects of exenatide at doses of 0.3 and 0.6 µg/kg (Figure 5G). The mean concentrations of LY3502970 and exenatide required to reduce food intake were 8.3 ± 0.8 nmol/L and 83.1 ± 4.5 pmol/L, respectively (mean ± standard error, n = 8). These results indicate that oral administration of LY3502970 can achieve a similar food intake reduction effect as the injectable GLP-1 receptor agonist exenatide. In summary, the preclinical pharmacodynamic characteristics of LY3502970 are similar to those of marketed peptide GLP-1 receptor agonists, and it has pharmacokinetic characteristics suitable for oral administration in humans. Therefore, LY3502970 is currently being evaluated in an early clinical trial for its potential as an antidiabetic drug (Clinical Trial Registration No.: NCT04426474) [2].

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For the evaluation of the treatment regimen, each dose of octaglitazone resulted in a statistically significant reduction in glycated hemoglobin (A1C) levels. Regarding the key secondary endpoint of weight, both the 12 mg and 36 mg doses resulted in statistically significant weight reductions.
Glycated hemoglobin (A1C) reduction: 1.2% (3 mg), 1.5% (12 mg), 1.5% (36 mg), 0.4% (placebo)
Percentage of weight loss: 4.5% (3 mg), 5.8% (12 mg), 7.6% (36 mg), 1.7% (placebo)
Weight loss: 4.2 kg (9.3 lbs; 3 mg), 5.2 kg (11.5 lbs; 12 mg), 7.2 kg (15.8 lbs; 36 mg), 1.5 kg (3.4 lbs; placebo)
In the ACHIEVE-1 study, the overall safety profile of ofoglione was consistent with established GLP-1 inhibitors. The most common adverse events were gastrointestinal related and were generally mild to moderate. The most common adverse events in subjects treated with ofoglitazone (3 mg, 12 mg, and 36 mg) were diarrhea (19%, 21%, and 26%, compared to 9% in the placebo group), nausea (13%, 18%, and 16%, compared to 2% in the placebo group), dyspepsia (10%, 20%, and 15%, compared to 7% in the placebo group), constipation (8%, 17%, and 14%, compared to 4% in the placebo group), and vomiting (5%, 7%, and 14%, compared to 1% in the placebo group). The treatment discontinuation rates due to adverse events were 6% (3 mg), 4% (12 mg), and 8% (36 mg) in the ofoglitazone group, compared to 1% in the placebo group. No liver safety signals were observed. The results of the ACHIEVE-1 study will be presented at the 85th Scientific Session of the ADA and published in a peer-reviewed journal. Later this year, further results from the ACHIEVE Phase III clinical trial and the ATTAIN Phase III clinical trial evaluating oxaliplatin for weight management will be released. Eli Lilly expects to submit a marketing application for orforglipron for weight management to global regulatory agencies by the end of this year, and plans to submit a marketing application for the treatment of type 2 diabetes in 2026.
About Orforglipron
Orforglipron is an investigational once-daily oral small molecule (non-peptide) glucagon-like peptide-1 receptor agonist that can be taken at any time of day without restrictions on food and water intake. ⁵Orforglipron was discovered by Chugai Pharmaceutical Co., Ltd. and licensed by Eli Lilly in 2018. Chugai Pharmaceutical and Eli Lilly jointly published preclinical pharmacological data for the molecule. Eli Lilly is conducting a Phase III clinical trial of ozoglione for the treatment of type 2 diabetes and for weight management in obese or overweight adults with at least one weight-related disorder. It is also being investigated as a potential treatment for obese adults with obstructive sleep apnea and hypertension.
About ACHIEVE-1 and the ACHIEVE Clinical Trial Program
ACHIEVE-1 (NCT05971940) is a Phase 3, 40-week randomized, double-blind, placebo-controlled trial designed to compare the efficacy and safety of ozoglione 3 mg, 12 mg, and 36 mg monotherapy versus placebo in adult patients with type 2 diabetes whose blood glucose is not adequately controlled by diet and exercise alone. The trial randomized 559 participants in the United States, China, India, Japan, and Mexico to receive ozoglione 3 mg, 12 mg, or 36 mg or placebo in a 1:1:1:1 ratio. This study aimed to demonstrate that ofoglitazone (3 mg, 12 mg, 36 mg) was more effective than baseline in reducing glycated hemoglobin (HbA1c) after 40 weeks in patients with type 2 diabetes who had not taken any hypoglycemic agents or received insulin therapy for at least 90 days. Study participants had HbA1c levels between ≥7.0% and ≤9.5% and a body mass index (BMI) ≥23 kg/m². All participants in the ofoglitazone treatment group started the study with a once-daily dose of 1 mg, then gradually increased the dose at four-week intervals until a final randomized maintenance dose was reached: 3 mg (incrementing by 1 mg each time), 12 mg (incrementing by 1 mg, 3 mg, and 6 mg, respectively), or 36 mg (incrementing by 1 mg, 3 mg, 6 mg, 12 mg, and 24 mg, respectively). Flexible dosing was not permitted. The ACHIEVE Phase III global clinical development program for ofoglitazone has enrolled more than 6,000 patients with type 2 diabetes in five registration trials worldwide. The project was launched in 2023 and results are expected to be released later this year and in 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-demonstrated-statistically

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Oforglipron (LY3502970; GLP-1 receptor agonist1) is an orally effective non-peptide GLP-1 receptor agonist developed from a pyrazolopyridine derivative [1,2]. Its mechanism of action involves binding to the extracellular domain of GLP-1R, inducing conformational changes in the receptor, activating the Gs protein signaling pathway, leading to cAMP accumulation, glucose-dependent insulin secretion, reduced glucagon release, and appetite suppression [2]. Structural studies have shown that ozoglione (LY3502970; GLP-1 receptor agonist 1) binds to the ortho site of GLP-1R, forms hydrogen bonds with Tyr138, Asp198 and Gln234 residues, and forms hydrophobic interactions with Phe192 and Trp287, thereby conferring high affinity and agonist activity [2]. This compound is expected to be used to treat type 2 diabetes and obesity, with the advantages of oral administration (superior to peptide GLP-1 agonists) and good pharmacokinetics and safety [1,2].

C48H48F2N10O5

882

882.377

C, 65.29; H, 5.48; F, 4.30; N, 15.86; O, 9.06

2212020-52-3

2212020-52-3 (free);2415797-61-2 (calcium); 3008544-96-2; 2212021-26-4 (calcium hydrate);

137319706

White to light yellow solid powder

6.8

1

10

7

65

1950

4

FC1C(C)=CC(=CC=1C)N1C(=C2C(CCN([C@H]2C)C(C2=CC3C=C([C@H]4CCOC(C)(C)C4)C=CC=3N2[C@@]2(C3NOC(N3)=O)C[C@@H]2C)=O)=N1)N1C=CN(C2C=CC3=C(C=NN3C)C=2F)C1=O

USUWIEBBBWHKNI-KHIFEHGGSA-N

InChI=1S/C48H48F2N10O5/c1-25-18-32(19-26(2)40(25)49)60-42(58-16-15-57(46(58)63)37-11-10-36-33(41(37)50)24-51-55(36)7)39-28(4)56(14-12-34(39)53-60)43(61)38-21-31-20-29(30-13-17-64-47(5,6)23-30)8-9-35(31)59(38)48(22-27(48)3)44-52-45(62)65-54-44/h8-11,15-16,18-21,24,27-28,30H,12-14,17,22-23H2,1-7H3,(H,52,54,62)/t27-,28-,30-,48-/m0/s1

3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one

GLP-1 receptor agonist 1; 2212020-52-3; LY3502970; CHEMBL4446782; LY-3502970; Orforglipron (USAN); ORFORGLIPRON [USAN];

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~113.26 mM)

Solubility in Formulation 1: ≥ 2 mg/mL (2.27 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2 mg/mL (2.27 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)