TPN171
目录号 : GC37817
TPN171 是一种有效选择性的、有口服活性的五型磷酸二酯酶 (PDE5) 抑制剂，IC50 值为 0.62 nM，被开发用于肺动脉高压 (PAH) 的治疗。
Cas No.:1229018-87-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
TPN171 is a potent, selective and oral bioavailable inhibitor of phosphodiesterase type 5 (PDE5) with an IC50 of 0.62 nM, being developed for the treatment of pulmonary arterial hypertension (PAH)[1]. PDE5|0.62 nM (IC50)
[1]. Wang Z, et al. Pharmacokinetics-Driven Optimization of 4(3 H)-Pyrimidinones as Phosphodiesterase Type 5 Inhibitors Leading to TPN171, a Clinical Candidate for the Treatment of Pulmonary Arterial Hypertension. J Med Chem. 2019 May 23;62(10):4979-4990.
| Cas No. | 1229018-87-4 | SDF | |
| Canonical SMILES | CCCOC1=C(C2=NC(CC)=C(CC)C(N2)=O)C=C(NC(CN3CCN(C)CC3)=O)C=C1 | ||
| 分子式 | C24H35N5O3 | 分子量 | 441.57 |
| 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 | 2.2646 mL | 11.3232 mL | 22.6465 mL |
| 5 mM | 0.4529 mL | 2.2646 mL | 4.5293 mL |
| 10 mM | 0.2265 mL | 1.1323 mL | 2.2646 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。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Characterization of TPN171 metabolism in humans via ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry
J Pharm Biomed Anal 2019 Aug 5;172:302-310.PMID:31079024DOI:10.1016/j.jpba.2019.05.001.
TPN171 is a novel potent pyrimidinone phosphodiesterase type 5 (PDE5) inhibitor with high selectivity and long duration of action. It has been used to treat patients suffering from pulmonary arterial hypertension and entered phase I clinical trials in 2016. Considering the potential therapeutic value of TPN171, its metabolism in humans is necessary to be elucidated during early-stage of drug development. This study aimed to establish a rapid and reliable method based on ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry for the characterization of TPN171 metabolites in human plasma, urine and stool samples. A total of 17 metabolites, including 14 from phase I and 3 from phase II metabolic reactions, were identified and characterized. TPN171 was found to be the predominant component in all plasma, urine and stool samples. Seven proposed metabolites were validated by comparing with synthetic reference standards. N-demethylation, O-depropylation, N-oxidation and dehydrogenation were demonstrated to be the main metabolic pathways of TPN171 in humans, yielding metabolites M4, M3, M7-2 and M5-3, respectively. Notably, M5-3 (a dehydrogenation product) and M3 (an O-depropylation product) were the main metabolites in human plasma while M5-3 (produced via dehydrogenation) and M7-2 (produced via N-oxidation) were the major metabolites in human urine. Besides, O-depropylation product M3 and N-demethylation product M4 were the main metabolites in human stool. In overall, this study assessed the metabolic fate of TPN171 in humans, which may yield considerably benefits for subsequent studies focusing on TPN171 metabolism and development of other PDE5 inhibitors.
Liquid chromatography-tandem mass spectrometric assay for TPN171 in human plasma
J Pharm Biomed Anal 2020 Nov 30;191:113634.PMID:32987249DOI:10.1016/j.jpba.2020.113634.
A simple, rapid and accurate method for quantitative analysis of a highly selective phosphodiesterase-5 inhibitor (PDE5), TPN171 by high performance liquid chromatography and tandem mass spectrometry in human plasma was proposed and validated successfully using D3-TPN171 as internal standards (ISTD). An aliquot of 100 μL of plasma was mixed with internal standard and was precipitated with acetonitrile. Gradient elution was performed on a ACQUITY HSS T3 column (50 × 2.1 mm, 1.8 μm) coupled with a ACQUITY column in-line filter at 40℃, by 5 mM ammonium acetate in water containing 0.1 % formic acid and 0.1 % formic acid in acetonitrile as the mobile phase. The total analytical run time was 3.5 min. The analyte was monitored using multiple reaction monitoring (MRM) scan in positive polarity mode. The ion transition was m/z 442.2→113.2 and 445.2→116.2 for TPN171 and D3-TPN171 respectively. The method was validated for specificity, sensitivity, precision, accuracy, and other analytical parameters. The results found were satisfactory over the linear calibration range of 1-500 ng/mL. Within-day precisions ranged from 1.8 to 7.3 %, and between-day precisions from 2.3 to 4.9 %, accuracies were 95.5-99.8 %.The validated method was successfully applied to determine the plasma concentration after oral administration of 10 mg TPN171 in six healthy volunteers.
Radiosynthesis of a carbon-11 labeled PDE5 inhibitor [11C]TPN171 as a new potential PET heart imaging agent
Appl Radiat Isot 2020 Aug;162:109190.PMID:32501230DOI:10.1016/j.apradiso.2020.109190.
To develop PET tracers for imaging of heart disease, a new carbon-11 labeled potent and selective PDE5 inhibitor [11C]TPN171 ([11C]9) has been synthesized. The reference standard TPN171 (9) and its corresponding precursor desmethyl-TPN171 (11) were synthesized from methyl 3-oxovalerate and 2-hydroxybenzonitrile in 9 and 10 steps with 31% and 25% overall chemical yield, respectively. The radiotracer [11C]TPN171 was prepared from desmethyl-TPN171 with [11C]CH3OTf through N-11C-methylation and isolated by HPLC purification followed by SPE formulation in 45-55% radiochemical yield, based on [11C]CO2 and decay corrected to EOB. The radiochemical purity was >99%, and the molar activity (Am) at EOB was in a range of 370-740 GBq/μmol.
Pharmacokinetics-Driven Optimization of 4(3 H)-Pyrimidinones as Phosphodiesterase Type 5 Inhibitors Leading to TPN171, a Clinical Candidate for the Treatment of Pulmonary Arterial Hypertension
J Med Chem 2019 May 23;62(10):4979-4990.PMID:31021628DOI:10.1021/acs.jmedchem.9b00123.
Phosphodiesterase type 5 (PDE5) inhibitors are first-line therapy for pulmonary arterial hypertension (PAH) and erectile dysfunction. As a continuing work to improve the terminal half-lives and oral bioavailabilities of our previously reported 4(3 H)-pyrimidones, a pharmacokinetics-driven optimization focusing on the terminal substituent is described. Two major congeneric series of 4(3 H)-pyrimidones, the aminosulfonylphenylpyrimidones and acylaminophenylpyrimidones, were designed, synthesized, and pharmacologically assessed in vitro and in vivo. Among them, compound 15 (TPN171) with subnanomolar potency for PDE5 and good selectivity over PDE6 was finally recognized as a potential drug candidate, and its pharmacokinetic profiles in rats and dogs are significantly improved compared to the starting compound (3). Moreover, TPN171 was proven to exert a longer lasting effect than sildenafil in animal models, providing a foundation for a once-daily oral administration for its clinical use. TPN171 is currently being investigated in a phase II clinical trial for the treatment of PAH.
Pharmacokinetics, mass balance, and metabolism of [14C]TPN171, a novel PDE5 inhibitor, in humans for the treatment of pulmonary arterial hypertension
Acta Pharmacol Sin 2023 Jan;44(1):221-233.PMID:35676531DOI:10.1038/s41401-022-00922-6.
TPN171 is a novel phosphodiesterase-5 (PDE5) inhibitor used to treat pulmonary arterial hypertension (PAH) and erectile dysfunction (ED), which currently is undergoing phase II clinical trials in China. In this single-center, single-dose, nonrandomized, and open design study, radiolabeled [14C]TPN171 was used to investigate the metabolic mechanism, pharmacokinetic characteristics, and clearance pathways of TPN171 in 6 healthy Chinese male volunteers. Each volunteer was administered a single oral suspension of 10 mg (100 μCi) of [14C]TPN171. We found that TPN171 was absorbed rapidly in humans with a peak time (Tmax) of 0.667 h and a half-life (t1/2) of approximately 9.89 h in plasma. Excretion of radiopharmaceutical-related components was collected 216 h after administration, accounting for 95.21% of the dose (46.61% in urine and 48.60% in feces). TPN171 underwent extensive metabolism in humans. Twenty-two metabolites were detected in human plasma, urine, and feces using a radioactive detector combined with a high-resolution mass spectrometer. According to radiochromatograms, a glucuronide metabolite of O-dealkylated TPN171 exceeded 10% of the total drug-related components in human plasma. However, according to the Food and Drug Administration (FDA) guidelines, no further tests are needed to evaluate the safety of this metabolite because it is a phase II metabolite, but the compound is still worthy of attention. The main metabolic biotransformation of TPN171 was mono-oxidation (hydroxylation and N-oxidation), dehydrogenation, N-dealkylation, O-dealkylation, amide hydrolysis, glucuronidation, and acetylation. Cytochrome P450 3A4 (CYP3A4) mainly catalyzed the formation of metabolites, and CYP2E1 and CYP2D6 were involved in the oxidative metabolism of TPN171 to a lesser extent. According to the incubation data, M1 was mainly metabolized to M1G by UDP-glucuronosyltransferase 1A9 (UGT1A9), followed by UGT1A7 and UGT1A10.