Gosogliptin (PF-00734200)
(Synonyms: (3,3-二氟吡咯烷-1-基)[(2S,4S)-4-[4-(嘧啶-2-基)哌嗪-1-基]吡咯烷-2-基]甲酮,PF-00734200; PF-734200) 目录号 : GC31463
An inhibitor of DPP-4
Cas No.:869490-23-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Kinase experiment: | Studies to identify the P450 isoform(s) responsible for formation of M5 are conducted using chemical inhibition and incubation in recombinant P450 isozymes. Inhibition studies are performed with each of the following inhibitors: Furafylline (10 μM for CYP1A2), Sulfaphenazole (10 μM for CYP2C9), Quinidine (10 μM for CYP2D6), (+)N-3-benzylnirvanol (10 μM for CYP2C19), and Ketoconazole (1 μM for CYP3A4). Incubations (1 ml) are performed in duplicate with NADPH (1.3 mM) in 1.5 mL plastic Eppendorf tubes open to air at 37°C in a shaking water bath. Samples are preincubated at 37°C for 5 min before the addition of NADPH. Each incubation contains microsomes (2 mg/mL protein), 100 mM potassium phosphate buffer (pH 7.4), 10 mM MgCl2, 10 μM Gosogliptin (PF-00734200), and one of the above inhibitors. A control sample is also prepared without inhibitor. Additional controls using marker substrates (each at 10 μM), in the presence and absence of P450-specific inhibitors, are used to confirm inhibition results and included Phenacetin (CYP1A2), Tolbutamide (CYP2C9), (S)-Mephenytoin (CYP2C19), Dextromethorphan (CYP2D6), and Testosterone (CYP3A4). At 0 and 30 min, incubations are quenched with an equal volume of ice-cold acetonitrile. Samples are then placed on ice for 15 min to allow precipitation of protein and subsequently centrifuged at 1800g for 5 min. An aliquot is removed from each sample and injected onto the HPLC/MS system[2]. |
Animal experiment: | Rats[2] A group of SD rats (n=3/gender) is administered a single 5 mg/kg oral dose of [14C] Gosogliptin for the mass balance study. For biliary excretion experiments, another group of two male and two female bile duct-cannulated rats is administered a single 5 mg/kg oral dose of [14C] Gosogliptin in similar fashion. The dose is formulated as a suspension in 0.5% methyl cellulose on the day before dose administration. Each rat received an approximate dose of ∼60 μCi of radiolabeled material. Urine and feces are collected from intact animals for 7 days at 0 to 8, 8 to 24, 24 to 48, 48 to 72, 72 to 96, 96 to 120, 120 to 144, and 144- to 168-h intervals after the dose. The first feces sample is collected at 0 to 24 h after the dose. Bile and urine samples are collected from bile duct-cannulated animals at 0- to 8-, 8- to 24-, and 24- to 48-h intervals after the dose. The volumes of urine and bile samples are recorded, and all of the biological samples are stored at -20°C until analysis. For determination of pharmacokinetic parameters and identification of circulating metabolites, a third group of jugular vein-cannulated rats (n=10/gender) is given an oral dose of 5 mg/kg [14C] Gosogliptin. Blood from two animals per gender is collected at 0.5, 1, 2, 4, and 8 h postdose in heparinized (lithium heparin anticoagulant) tubes. The blood samples are centrifuged at 1000g for 10 min to obtain the plasma. Plasma is transferred to clean tubes and stored at -20°C until analysis. |
References: [1]. Dai H, et al. The pharmacokinetics of PF-734200, a DPP-IV inhibitor, in subjects with renal insufficiency. Br J Clin Pharmacol. 2011 Jul;72(1):85-91. | |
Gosogliptin is an inhibitor of dipeptidyl peptidase 4 (DPP-4; IC50 = 0.013 ?M).1 It is selective for DPP-4 over DPP-2, -3, -8, and -9 (IC50s = 3.3, >30, 7, and 5.98 ?M, respectively), the serine proteases APP, FAP, and POP (IC50s = >30, 10.3, and >30 ?M, respectively), and a panel of enzymes, receptors, and ion channels (IC50s = >10 ?M for all).
1.Ammirati, M.J., Andrews, K.M., Boyer, D.D., et al.(3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone: A potent, selective, orally active dipeptidyl peptidase IV inhibitorBioorg. Med. Chem. Lett.19(7)1991-1995(2009)
| Cas No. | 869490-23-3 | SDF | |
| 别名 | (3,3-二氟吡咯烷-1-基)[(2S,4S)-4-[4-(嘧啶-2-基)哌嗪-1-基]吡咯烷-2-基]甲酮,PF-00734200; PF-734200 | ||
| Canonical SMILES | O=C([C@H](C1)NC[C@H]1N2CCN(CC2)C3=NC=CC=N3)N4CC(CC4)(F)F | ||
| 分子式 | C17H24F2N6O | 分子量 | 366.41 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.7292 mL | 13.6459 mL | 27.2918 mL |
| 5 mM | 0.5458 mL | 2.7292 mL | 5.4584 mL |
| 10 mM | 0.2729 mL | 1.3646 mL | 2.7292 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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The pharmacokinetics and pharmacodynamics of PF-00734200, a DPP-IV inhibitor, in healthy Japanese subjects
Objective: To evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of PF-00734200, a potent dipeptidyl peptidase-IV (DPP-IV) inhibitor, in Japanese subjects, and compare the results with those in Western subjects. Materials and methods: Eight healthy Japanese subjects received a single dose of PF-00734200 10 mg, 100 mg, or placebo. Another 8 subjects received PF-00734200 20 mg or placebo single dose once daily for 6 days. Serum and urine PK, plasma DPP-IV activity, and plasma glucagon-like peptide 1 (GLP-1) levels were measured. Results: Linear pharmacokinetics was observed over the single dose range 10 - 100 mg. Following multiple-dose administration, 37.3 ± 4.33% of the unchanged PF-00734200 was excreted in the urine and renal clearance was calculated as 33.9 ± 6.56 ml/min. After the standardized meals, GLP- 1 levels increased ~ 2-fold compared with placebo, and no further increase in GLP-1 levels was observed at doses above 10 mg. The steady state DPP-IV inhibition at 24 h was ~ 75%. Conclusion: Pharmacokinetics of PF-00734200, inhibition of DPP-IV, and non-linear increases in GLP-1 were similar between healthy Japanese and Western subjects.
Dipeptidyl Peptidase-4 Inhibitors
The dipeptidyl peptidase 4 (DPP-4) inhibitors are a family of diabetic agents that enhance glucagon-like peptide-1 (GLP-1) activity, a gastrointestinal hormone (incretin) that increases glucose dependent insulin secretion. The DPP-4 inhibitors decrease the degradation of GLP-1 and thereby increase endogenous circulating levels. The increase levels of GLP-1 in the circulation increase pancreatic insulin secretion and improve glycemic control in patients with type 2 diabetes. The DPP-4 inhibitors have only recently been introduced into clinical use and the full range of adverse events may not be fully known. However, in prelicensure clinical trials, sitagliptin, saxagliptin, linagliptin and alopgliptin, the first four DPP-4 inhibitors to receive FDA approval in the United States, were not associated with an increase in serum aminotransferase or alkaline phosphatase elevations above the rates found in controls, and no clinically apparent acute liver injury was reported. Since licensure, isolated case reports of liver injury have arisen but liver injury from these agents appears to be rare and generally mild.
As of 2018, the four DPP-4 inibitors that are available in the United States include (with brand names and year of approval): sitagliptin (Januvia, 2006), saxagliptin (Onglyza, 2009), linagliptin (Tradjenta, 2011) and alogliptin (Nesina, 2013). These four DPP-4 inhibitors are discussed individually in LiverTox, but references to their safety and potential hepatotoxicity are given together after this introductory section. DDP-4 inhibitors in clinical use in other countries include vildagliptin, gemigliptin, anagliptin, omarigliptin, evogliptin, gosogliptin and teneligliptin.
The four DDP-4 inhibitors have been linked to rare instances of self-limited, cholestatic or mixed liver injury that generally arises 1 to 4 weeks after initiation of therapy and resolves without residual injury within 1 to 3 months.
Metabolism, excretion, and pharmacokinetics of ((3,3-difluoropyrrolidin-1-yl)((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone, a dipeptidyl peptidase inhibitor, in rat, dog and human
The disposition of 3,3-difluoropyrrolidin-1-yl{(2S,4S)-4-[4-(pyrimidin-2-yl)piperazin-1-yl]pyrrolidin-2-yl}methanone (PF-00734200), a dipeptidyl peptidase IV inhibitor that progressed to phase 3 for the treatment of type 2 diabetes, was examined in rats, dogs, and humans after oral administration of a single dose of [(14)C]PF-00734200. Mean recoveries of administered radioactivity were 97.1, 92.2, and 87.2% in rats, dogs, and humans, respectively. The majority of radioactive dose was detected in the urine of dogs and humans and in the feces of rats. Absorption of PF-00734200 was rapid in all species, with maximal plasma concentrations of radioactivity achieved within 1 h after the dose. Circulating radioactivity was primarily composed of the parent drug (79.9, 80.2, and 94.4% in rat, dog, and human, respectively). The major route of metabolism was due to hydroxylation at the 5' position of the pyrimidine ring (M5) in all species. In vitro experiments with recombinant cytochrome P450 isoforms suggested that the formation of M5 was catalyzed both by CYP2D6 and CYP3A4. Molecular docking simulations showed that the 5' position of the pyrimidine moiety of PF-00734200 can access the heme iron-oxo of both CYP3A4 and CYP2D6 in an energetically favored orientation. Other metabolic pathways included amide hydrolysis (M2), N-dealkylation at the piperazine nitrogen (M3) and an unusual metabolite resulting from scission of the pyrimidine ring (M1). Phase II metabolic pathways included the following: carbamoyl glucuronidation (M9), glucosidation (M15) on the pyrrolidine nitrogen, and conjugation with creatinine to form an unusual metabolite/metabonate (M16). The data from these studies suggest that PF-00734200 is eliminated by both metabolism and renal clearance.
[Cerebroprotective activity of metformin, gosogliptin, citicoline and a novel GPR119 agonist in cerebral ischemia under experimental diabetes mellitus]
Hypoglycemic agents of some groups: sodium-glucose cotransporter type 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists reduce the risk and/or severity of cardiovascular diseases. Studies of such properties are currently focused on metformin and dipeptidyl peptidase-4 (DPP-4) inhibitors. Agonists of GPR119 receptor, increasing the secretion of GLP-1 and insulin, are also actively studied as hypoglycemic drugs with endothelial and cerebroprotective potential.
Aim: To evaluate the cerebroprotective activity of metformin, gosogliptin, citicoline and an agonist of GPR119 (ZB-16) in middle cerebral artery occlusion (MCAO) in animals with 4-week streptozotocin-nicotinamide-induced diabetes.
Material and methods: A study included 73 male rats. Hypoglycemic agents and ZB-16 were administered on the first day of diabetes and citicoline was administered after MCAO. Cerebroprotective effect was evaluated using Garcia, Combs and D'Alecy score test, 'Rotarod' and 'open field' test, as well as the infarct volume and severity of brain edema measurement.
Results and conclusion: Preventive administration of metformin resulted in the pronounced hypoglycemic activity without a significant cerebroprotective effect in subsequent brain ischemia modelling. Administration of substances with incretin activity (gosogliptin and, in particular, ZB-16) in addition to the hypoglycemic action promoted a significant reduction of infarct volume, brain edema and severity of neurologic deficit of the surviving animals. At the same time, the introduction of citicoline without proper glycemic control didn't reduce the brain ischemia severity.