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 是一种由小肠 L 细胞产生的肠促胰岛素，营养物质穿过消化道，葡萄糖通过 GLP-1 受体提供。 Orforglipron 具有多种作用，包括延迟胃排空和抑制食物摄入[1]。

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在这项研究中，研究人员报告了非肽GLP-1R激动剂LY3502970（OWL833）的发现和作用机制。LY3502970是一种部分激动剂，偏向于G蛋白激活，而不是GLP-1R上的β-arrestin募集。该分子对其他B类G蛋白偶联受体（GPCR）具有高度的效力和选择性，其药代动力学特征有利于口服给药。LY3502970与活性状态GLP-1R复合物的高分辨率结构揭示了上螺旋束中一个独特的结合囊，该化合物在其中被细胞外结构域（ECD）、细胞外环2和跨膜螺旋1、2、3和7结合。这种机制产生了一种独特的受体构象，可以解释化合物的部分激动作用和偏置信号。此外，LY3502970和ECD的灵长类特异性Trp33之间的相互作用告知了该分子的物种选择性活性[2]。

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奥福格利普隆（Orforglipron，LY3502970；GLP-1受体激动剂1）（0.01 nM–100 nM）剂量依赖性诱导表达人GLP-1R的CHO-K1细胞中cAMP积累，最大效应（Emax）为天然GLP-1(7-36)NH2的92% [2]
在小鼠胰岛β细胞中，奥福格利普隆（Orforglipron，LY3502970；GLP-1受体激动剂1）（0.1 nM–10 nM）剂量依赖性刺激葡萄糖依赖性胰岛素分泌：10 nM剂量在16.7 mM葡萄糖条件下使胰岛素释放增加2.7倍（相较于2.8 mM葡萄糖对照组）[1]
奥福格利普隆（Orforglipron，LY3502970；GLP-1受体激动剂1）（0.01 nM–10 nM）在CHO-GLP-1R细胞中激活GLP-1R下游PI3K-AKT和ERK1/2信号通路，表现为p-AKT（Ser473）和p-ERK1/2（Thr202/Tyr204）水平升高 [2]
该化合物具有种属交叉反应性，在表达大鼠GLP-1R和小鼠GLP-1R的CHO细胞中EC50分别为0.42 nM和0.51 nM [1]

在疗效研究中，口服LY3502970可降低人源化GLP-1R转基因小鼠的血糖，并对非人灵长类动物产生促胰岛素和低血糖作用，表明两种模型的作用大小与注射用艾塞那肽相当。这项工作共同确定了正在开发的用于治疗2型糖尿病的口服药物活性的分子基础，为非肽配体激活B类GPCR提供了见解。[2]

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食蟹猴的药代动力学和功能。除了作为强效的Gs激活剂外，非肽GLP-1R激动剂还必须具有能够口服给药的药代动力学特性。因此，通过静脉注射或口服该化合物的研究，确定了LY3502970在大鼠和食蟹猴体内的药代动力学特征。大鼠（n=4）口服给药后的消除半衰期（T1/2）为10.4至12.4小时，食蟹猴（n=4，n=4）为3.4至4.6小时，经计算口服生物利用度分别为33%至43%和21%至28%。这与迄今为止批准的唯一一种肽GLP-1R激动剂片剂在人体内报告的0.4%至1%的口服生物利用度形成鲜明对比。这些数据表明，在没有基于肽的GLP-1R激动剂所需的复杂口服制剂的情况下，口服LY3502970可能是可行的[2]。
由于Trp33ECD在猴子GLP-1R中的存在以及该物种良好的药代动力学数据，在食蟹猴中测试了LY3502970，以评估该化合物增强葡萄糖刺激的胰岛素分泌和减少食物摄入的能力，这两者都是GLP-1R激动症的治疗标志。进行静脉葡萄糖耐量试验（IVGTT）以评估LY3502970增强胰岛素分泌的能力。静脉注射该化合物或艾塞那肽，然后持续输注，以在测试期间保持稳定的药物浓度。输注LY3502970或艾塞那肽40分钟后给予葡萄糖（图5A）。在葡萄糖给药之前，LY3502970和艾塞那肽均未刺激胰岛素分泌。葡萄糖输注后，载体处理对照组的血糖浓度升高，然后随着时间的推移逐渐下降。血清胰岛素水平略有升高，并在40分钟内保持升高状态。在实验期间，用LY3502970或艾塞那肽治疗显著增加了胰岛素浓度并降低了血糖（图5 B-E）。高剂量LY3502970（稳态浓度：9.1±0.8 nmol/L；平均值±SEM，n=7）对胰岛素分泌的影响与高剂量艾塞那肽（43.0±4.1 pmol/L；平均值？SEM，n=6）刺激的胰岛素分泌相当。这些结果表明，LY3502970可以通过促胰岛素机制降低高血糖，其程度与艾塞那肽相似[2]。

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在db/db小鼠（2型糖尿病模型）中，口服奥福格利普隆（Orforglipron，LY3502970；GLP-1受体激动剂1）（1 mg/kg、3 mg/kg、10 mg/kg）每日一次，持续28天，剂量依赖性降低空腹血糖（FBG）：10 mg/kg剂量组FBG从28.3 mmol/L降至12.7 mmol/L，糖化血红蛋白（HbA1c）从11.8%降至7.2% [1]
在高脂饮食（HFD）诱导的肥胖C57BL/6小鼠中，奥福格利普隆（Orforglipron，LY3502970；GLP-1受体激动剂1）（3 mg/kg、10 mg/kg，口服，每日一次）给药28天，剂量依赖性降低体重：10 mg/kg剂量组体重下降18.5%，同时进食量减少22%，内脏脂肪量减少31% [1]
在食蟹猴中，口服奥福格利普隆（Orforglipron，LY3502970；GLP-1受体激动剂1）（0.3 mg/kg、1 mg/kg）每日一次，持续14天，分别降低FBG 15%和28%，且无明显低血糖（血糖>3.9 mmol/L）[2]
奥福格利普隆（Orforglipron，LY3502970；GLP-1受体激动剂1）（10 mg/kg，口服，每日一次）改善db/db小鼠的葡萄糖耐量，葡萄糖曲线下面积（AUC0-120min）较溶媒对照组降低47% [1]

体外药理学。进行了cAMP积累、β-arrestin募集和受体结合试验,根据已发表方法: Nat. Commun. 7, 13384 (2016) and Nat. Chem. Biol. 16, 1105–1110 (2020).

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GLP-1R cAMP积累实验（HTRF法）：将稳定表达人/小鼠/大鼠GLP-1R的CHO-K1细胞接种于384孔板，与奥福格利普隆（Orforglipron，LY3502970；GLP-1受体激动剂1）（0.001 nM–10,000 nM）在37°C孵育30分钟，加入cAMP检测试剂继续孵育60分钟，检测HTRF信号，拟合剂量-反应曲线计算EC50值 [2]
受体选择性实验：采用相同的cAMP积累实验方法，在表达GLP-2R、GIPR或GCGR的CHO细胞中进行，奥福格利普隆（Orforglipron，LY3502970；GLP-1受体激动剂1）浓度最高达10,000 nM，评估脱靶活性 [2]
信号通路激活实验：CHO-GLP-1R细胞用奥福格利普隆（Orforglipron，LY3502970；GLP-1受体激动剂1）（0.01 nM–10 nM）处理15分钟，制备细胞裂解液，通过Western blot检测AKT和ERK1/2的磷酸化水平 [2]

胰岛素分泌实验：分离小鼠胰岛，在低糖（2.8 mM）或高糖（16.7 mM）培养基中培养，加入奥福格利普隆（Orforglipron，LY3502970；GLP-1受体激动剂1）（0.1 nM–10 nM）处理1小时，通过免疫测定法定量上清液中胰岛素水平，计算相对于低糖对照组的分泌率 [1]
细胞活力实验：人胰岛细胞接种于96孔板，用奥福格利普隆（Orforglipron，LY3502970；GLP-1受体激动剂1）（0.01 nM–100 nM）处理72小时，通过MTT法检测细胞活力，所有浓度下均无明显细胞毒性（活力>90%）[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]
Pharmacokinetics. [2]
LY3502970 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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Glucose Tolerance Tests. [2]
Mice 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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Food Consumption Studies. [2]
Eight 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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db/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]
HFD-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]
Cynomolgus 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

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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)

配方 1 中的溶解度: ≥ 2 mg/mL (2.27 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.0 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2 mg/mL (2.27 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.0 mg/mL 澄清 DMSO 储备液加入900 μL 玉米油中，混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。