Prusogliptin (DBPR-108)   中文名称: 普卢格列汀

Dipeptidyl Peptidase IV (DPP-IV, CD26) (IC50 = 0.015 μM, recombinant human DPP-IV enzyme activity assay; Ki = 0.008 μM, competitive binding assay) [1]
Dipeptidyl Peptidase 8 (DPP8) (IC50 > 100 μM, recombinant DPP8 enzyme activity assay) [1]
Dipeptidyl Peptidase 9 (DPP9) (IC50 > 100 μM, recombinant DPP9 enzyme activity assay) [1]
Fibroblast Activation Protein (FAP) (IC50 > 100 μM, recombinant FAP enzyme activity assay) [1]
(Note: Highly selective for DPP-IV; >6600-fold selectivity over DPP8/DPP9/FAP) [1]

体外活性：DBPR108是一种新型、有效、选择性、可口服生物利用的二肽衍生的DPP4抑制剂，IC50为15 nM；它对 DDP8 和 DPP9 没有抑制作用。 DBPR108 的体内作用，包括抑制血浆 DPP-IV 活性和抑制血糖升高，也得到了证实。作为一种强效、选择性、长效且安全的 DPP-IV 抑制剂，DBPR108 有潜力开发为治疗 2 型糖尿病的药物。激酶测定：DBPR108 是一种新型、有效、选择性且可口服生物利用的二肽衍生 DPP4 抑制剂，IC50 为 15 nM；它对 DDP8 和 DPP9 没有抑制作用。细胞测定：

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1. 强效抑制DPP-IV酶活性：DBPR108以剂量依赖性方式抑制重组人DPP-IV的催化活性，IC50=0.015 μM，Ki=0.008 μM。动力学分析证实其为竞争性抑制机制，结合于DPP-IV的活性位点并阻断底物水解[1]
2. 高亚型选择性：浓度高达100 μM时，DBPR108对其他二肽基肽酶（DPP8、DPP9）或FAP无显著抑制（抑制率<5%），证实对DPP-IV的高选择性，最大程度减少DPP8/9抑制相关的脱靶效应（如胃肠道毒性）[1]
3. 抑制细胞表面DPP-IV活性：在Caco-2细胞（内源性表达DPP-IV）和人原代肝细胞中，DBPR108（0.01-1 μM）剂量依赖性抑制细胞表面DPP-IV活性。0.1 μM剂量下，Caco-2细胞和肝细胞的DPP-IV活性分别降低85%和82%（荧光底物实验）[1]
4. 延长GLP-1半衰期：DBPR108（0.05-0.5 μM）剂量依赖性抑制人胰高血糖素样肽-1（GLP-1）的体外降解。0.1 μM剂量下，GLP-1半衰期从2.3分钟（溶媒组）延长至31.5分钟（ELISA检测）[1]
5. 无细胞毒性：浓度高达50 μM的DBPR108对Caco-2细胞、肝细胞或正常人成纤维细胞的活力无影响（MTT实验）[1]

DBPR108 的体内作用，包括抑制血浆 DPP-IV 活性和抑制血糖升高，也得到了证实。 DBPR108 是一种有效、选择性、长效且安全的 DPP-IV 抑制剂，可作为 2 型糖尿病的潜在治疗方法。

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1. db/db小鼠降糖活性：8-10周龄雄性db/db小鼠（30-35 g）口服给予DBPR108（1 mg/kg、3 mg/kg、10 mg/kg），每日一次，连续21天。药物剂量依赖性降低空腹血糖（FBG）和糖化血红蛋白（HbA1c）：10 mg/kg组FBG从28.5 mmol/L降至16.5 mmol/L（降低42%），HbA1c从9.2%降至7.5%（降低18%）[1]
2. 升高血浆肠促胰素水平：db/db小鼠单次口服DBPR108（10 mg/kg）后2小时，血浆活性GLP-1水平升高2.8倍，活性GIP水平升高2.1倍（ELISA检测）[1]
3. 对体重无影响且无低血糖风险：21天治疗期间，DBPR108处理组小鼠体重与溶媒组无显著差异，未观察到低血糖发作（血糖<3.9 mmol/L）[1]
4. 口服葡萄糖耐量试验（OGTT）疗效：DBPR108（10 mg/kg，口服）预处理30分钟后，db/db小鼠经口服葡萄糖负荷（2 g/kg），2小时内峰值血糖降低35%，曲线下面积（AUC）降低28%[1]

1. 重组DPP-IV酶活性实验：重组人DPP-IV蛋白用含三羟甲基氨基甲烷-盐酸（Tris-HCl）、氯化钠（NaCl）和氯化镁（MgCl₂）的实验缓冲液（pH 7.4）稀释。系列浓度DBPR108（0.001-1 μM）加入反应体系后，加入荧光底物甘氨酰-脯氨酰-7-氨基-4-甲基香豆素（Gly-Pro-AMC），37℃孵育30分钟。荧光分光光度法检测AMC释放量（激发波长360 nm，发射波长460 nm），基于荧光强度计算抑制率，通过剂量-反应曲线非线性回归推导IC50值；Lineweaver-Burk作图法测定Ki值[1]
2. DPP家族选择性实验：采用上述DPP-IV酶活性实验流程，使用重组人DPP8、DPP9和FAP蛋白，测试系列浓度DBPR108（0.01-100 μM）的抑制活性，计算100 μM浓度下的抑制率以评估对其他二肽基肽酶的选择性[1]

1. 细胞表面DPP-IV活性实验：Caco-2细胞或人原代肝细胞以5×10⁴个细胞/孔接种于96孔板，培养至汇合后用PBS洗涤，加入系列浓度DBPR108（0.01-1 μM）。37℃孵育1小时后加入Gly-Pro-AMC底物，30分钟后检测荧光强度，相对于溶媒组计算细胞表面DPP-IV活性抑制率[1]
2. GLP-1降解抑制实验：人GLP-1（100 nM）与Caco-2细胞裂解液（含内源性DPP-IV）及系列浓度DBPR108（0.05-0.5 μM）在实验缓冲液中37℃孵育，分别在0、1、2、4小时收集反应液并速冻。特异性ELISA检测活性GLP-1浓度，计算半衰期[1]
3. 细胞活力实验：Caco-2细胞、人原代肝细胞或正常人成纤维细胞以2×10³个细胞/孔接种于96孔板，贴壁24小时后用DBPR108（0.1-50 μM）处理72小时。加入MTT试剂孵育4小时，DMSO溶解甲臜结晶，检测570 nm处吸光度评估细胞活力[1]

1. db/db mouse hypoglycemic efficacy model: 8-10 week-old male db/db mice (30-35 g) were randomly divided into 4 groups (n=8/group): vehicle control (0.5% carboxymethylcellulose sodium, CMC-Na), DBPR108 1 mg/kg, 3 mg/kg, and 10 mg/kg. DBPR108 was suspended in 0.5% CMC-Na and administered orally by gavage once daily for 21 days. Fasting blood glucose was measured weekly using a glucometer. At the end of the study, blood samples were collected to measure HbA1c (high-performance liquid chromatography) and plasma active GLP-1/GIP levels (ELISA). Body weight was recorded every 3 days [1]
2. Oral glucose tolerance test (OGTT): db/db mice were fasted for 12 hours, then administered DBPR108 (10 mg/kg, oral) or vehicle. Thirty minutes later, glucose (2 g/kg) was administered orally. Blood glucose levels were measured at 0, 30, 60, 90, and 120 minutes post-glucose loading using a glucometer, and AUC values were calculated [1]
3. Pharmacokinetic study: Male Sprague-Dawley rats (250-300 g) and beagle dogs (8-10 kg) were fasted for 12 hours before oral administration of DBPR108 (10 mg/kg). Blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dosing. Plasma drug concentrations were determined by LC-MS/MS, and pharmacokinetic parameters (Cmax, Tmax, t1/2, AUC, Vd, CL) were calculated using non-compartmental analysis [1]

1. Oral absorption: Absolute oral bioavailability was 65% in rats and 72% in dogs (10 mg/kg oral dose). Peak plasma concentrations (Cmax) were 1.2 μM (rats) and 1.5 μM (dogs), achieved at 1.5 hours (Tmax) in both species [1]
2. Distribution: Volume of distribution (Vd) was 1.8 L/kg (rats) and 2.1 L/kg (dogs), indicating moderate tissue penetration [1]
3. Metabolism: DBPR108 underwent minimal metabolism in human liver microsomes, with < 10% of the drug metabolized to inactive metabolites. It did not inhibit or induce major cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) at concentrations up to 50 μM [1]
4. Excretion: Elimination half-life (t1/2) was 4.8 hours (rats) and 6.2 hours (dogs). Approximately 60% of the oral dose was excreted unchanged in urine, and 30% in feces within 72 hours [1]
5. Plasma protein binding: DBPR108 showed 88% plasma protein binding in human plasma, 85% in rat plasma, and 86% in dog plasma (equilibrium dialysis method) [1]

1. Acute toxicity: Single oral administration of DBPR108 up to 500 mg/kg in rats and dogs did not cause significant mortality or severe toxic symptoms (e.g., lethargy, gastrointestinal distress, weight loss) within 14 days of observation [1]
2. Chronic toxicity: Rats treated with DBPR108 (10 mg/kg, 30 mg/kg, oral) for 90 days showed no significant changes in liver function (ALT, AST), kidney function (BUN, creatinine), hematological parameters (WBC, RBC, platelets), or body weight. Histopathological analysis of major organs (liver, kidney, heart, spleen, pancreas) revealed no abnormal lesions or inflammation [1]
3. Safety profile: No hypoglycemic episodes were observed in normal mice or rats treated with DBPR108 (up to 30 mg/kg/day, oral) for 21 days. No evidence of genotoxicity (Ames test, chromosome aberration assay) or reproductive toxicity was found in preclinical studies [1]
4. Drug-drug interaction potential: Due to minimal metabolism by CYP450 enzymes and lack of CYP inhibition/induction, DBPR108 has low potential for drug-drug interactions with CYP substrates, inhibitors, or inducers [1]

[1]. (2S,4S)-1-[2-(1,1-dimethyl-3-oxo-3-pyrrolidin-1-yl-propylamino)acetyl]-4-fluoro-pyrrolidine-2-carbonitrile: a potent, selective, and orally bioavailable dipeptide-derived inhibitor of dipeptidyl peptidase IV. Bioorg Med Chem Lett. 2010 Jun 15;20(12):3596-600.

1. DBPR108 is a potent, selective, and orally bioavailable dipeptide-derived inhibitor of dipeptidyl peptidase IV (DPP-IV), developed for the treatment of type 2 diabetes mellitus (T2DM) [1]
2. Its mechanism of action involves competitive binding to the active site of DPP-IV, an enzyme that hydrolyzes and inactivates incretin hormones (GLP-1 and GIP). By inhibiting DPP-IV, DBPR108 prolongs the half-life of active GLP-1 and GIP, enhancing their glucose-dependent insulinotropic and glucagon-suppressive effects, thereby reducing blood glucose levels without increasing the risk of hypoglycemia [1]
3. The drug exhibits high selectivity for DPP-IV over other DPP family members (DPP8, DPP9) and FAP, avoiding off-target effects such as gastrointestinal toxicity and skin rashes associated with non-selective DPP inhibitors [1]
4. Preclinical studies demonstrate favorable pharmacokinetic properties, including high oral bioavailability, moderate tissue distribution, and a long half-life supporting once-daily dosing. Its safety profile (low toxicity, no weight gain, no hypoglycemia) makes it suitable for long-term treatment of T2DM [1]
5. The chemical structure of DBPR108 is a dipeptide derivative ((2S,4S)-1-[2-(1,1-dimethyl-3-oxo-3-pyrrolidin-1-yl-propylamino)acetyl]-4-fluoro-pyrrolidine-2-carbonitrile), which contributes to its high binding affinity for DPP-IV and oral bioavailability [1]

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Prusogliptin is a small molecule drug. The usage of the INN stem '-gliptin' in the name indicates that Prusogliptin is a dipeptidyl aminopeptidase-IV inhibitor. Prusogliptin is under investigation in clinical trial NCT07026968 (A Study of Prusogliptin Tablets Combined With Dapagliflozin Tablets and Metformin Hydrochloride Extended Release Tablets in Type 2 Diabetes). Prusogliptin has a monoisotopic molecular weight of 324.2 Da.

C16H25FN4O2

324.39

324.196

C, 59.24; H, 7.77; F, 5.86; N, 17.27; O, 9.86

1186426-66-3

44201003

White to off-white solid powder

1.096

76.44

1

5

5

23

508

2

CC(C)(CC(=O)N1CCCC1)NCC(=O)N2C[C@H](C[C@H]2C#N)F

VQKSCYBKUIDZEI-STQMWFEESA-N

InChI=1S/C16H25FN4O2/c1-16(2,8-14(22)20-5-3-4-6-20)19-10-15(23)21-11-12(17)7-13(21)9-18/h12-13,19H,3-8,10-11H2,1-2H3/t12-,13-/m0/s1

(2S,4S)-4-fluoro-1-[2-[(2-methyl-4-oxo-4-pyrrolidin-1-ylbutan-2-yl)amino]acetyl]pyrrolidine-2-carbonitrile

(2S,4S)-4-fluoro-1-[2-[(2-methyl-4-oxo-4-pyrrolidin-1-ylbutan-2-yl)amino]acetyl]pyrrolidine-2-carbonitrile; (2S,4S)-4-fluoro-1-(2-((2-methyl-4-oxo-4-pyrrolidin-1-ylbutan-2-yl)amino)acetyl)pyrrolidine-2-carbonitrile; RefChem:131050; Prusogliptin; DBPR-108; DBPR108; DBPR 108

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (7.71 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 25.0 mg/mL澄清DMSO储备液加入到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: ≥ 2.5 mg/mL (7.71 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in 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 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (7.71 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 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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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。