Tenapanor (hydrochloride)
(Synonyms: TENAPANORHCL(2盐),AZD1722 hydrochloride; RDX5791 hydrochloride) 目录号 : GC48336
A NHE-3 inhibitor
Cas No.:1234365-97-9
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
Tenapanor is an orally bioavailable inhibitor of sodium-hydrogen exchanger 3 (NHE-3; IC50 = 10 nM for the recombinant rat protein).1 Tenapanor (10 µM) inhibits intestinal fluid absorption in mouse jejunum, but not distal colon, in a closed intestine loop assay.2 It also lowers both the sodium and phosphate urinary-to-dietary ratio in a dose-dependent manner in rats.1 Tenapanor (5 mg/kg) reverses decreases in stool pellet numbers and water content induced by loperamide and prevents loperamide-induced constipation in mice.2 Formulations containing tenapanor have been used in the treatment of irritable bowel syndrome with constipation.
1.LabontÉ, E.D., Carreras, C.W., Leadbetter, M.R., et al.Gastrointestinal inhibition of sodium-hydrogen exchanger 3 reduces phosphorus absorption and protects against vascular calcification in CKDJ. Am. Soc. Nephrol.26(5)1138-1149(2015) 2.Haggie, P.M., Cil, O., Lee, S., et al.SLC26A3 inhibitor identified in small molecule screen blocks colonic fluid absorption and reduces constipationJCI Insight3(14)e121370(2018)
| Cas No. | 1234365-97-9 | SDF | |
| 别名 | TENAPANORHCL(2盐),AZD1722 hydrochloride; RDX5791 hydrochloride | ||
| Canonical SMILES | O=S(NCCOCCOCCNC(NCCCCNC(NCCOCCOCCNS(=O)(C1=CC=CC([C@@]2(CN(C)CC3=C(Cl)C=C(C=C23)Cl)[H])=C1)=O)=O)=O)(C4=CC([C@@]5([H])C6=CC(Cl)=CC(Cl)=C6CN(C5)C)=CC=C4)=O.Cl.Cl | ||
| 分子式 | C50H66Cl4N8O10S2•2HCl | 分子量 | 1218 |
| 溶解度 | DMSO : 100 mg/mL (82.10 mM; Need ultrasonic); H2O : 20 mg/mL (16.42 mM; Need ultrasonic) | 储存条件 | -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 | 0.821 mL | 4.1051 mL | 8.2102 mL |
| 5 mM | 0.1642 mL | 0.821 mL | 1.642 mL |
| 10 mM | 0.0821 mL | 0.4105 mL | 0.821 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。
Tenapanor hydrochloride for the treatment of constipation-predominant irritable bowel syndrome
Expert Opin Investig Drugs 2015;24(8):1093-9.PMID:26065434DOI:10.1517/13543784.2015.1054480.
Introduction: Constipation-predominant irritable bowel syndrome (IBS-C) is a common functional gastrointestinal (GI) disorder characterized by recurrent abdominal pain and prolonged GI transit. The pathogenesis of IBS-C has still not been established; therefore, drugs currently in use in IBS-C act mainly symptomatically, whereas novel pharmacological targets are urgently needed. Tenapanor is a potent inhibitor of Na(+)/H(+) exchanger 3 [NHE3], localized in the apical membrane of intestinal epithelial cells. NHE3 participates in the uptake of sodium ions and water from the intestinal lumen. Areas covered: In this review, the authors discuss pharmacodynamics and pharmacokinetics of Tenapanor, focusing on animal models and in vitro studies. They also summarize clinical trials on Tenapanor's safety and efficacy in view of its potential role in IBS-C therapy. Expert opinion: Tenapanor possesses an excellent preclinical safety profile and, as of now, there are no serious concerns about its side effects. The non-systemic action of Tenapanor constitutes a significant advantage, as it minimizes possible adverse effects or drug-drug interactions. However, Phase III clinical trials are still needed to confirm results obtained in earlier phases and optimize the dose-response for Tenapanor, whereas limiting diarrhea, its major adverse effect.
Predicting the Physical Stability of Amorphous Tenapanor hydrochloride Using Local Molecular Structure Analysis, Relaxation Time Constants, and Molecular Modeling
Mol Pharm 2019 Mar 4;16(3):943-951.PMID:30699296DOI:10.1021/acs.molpharmaceut.8b00853.
The conformational flexibility of organic molecules introduces more structural options for crystallization to occur but has potential complications, such as, reduced crystallization tendency and conformational polymorphism. Although a variety of energetically similar conformers could be anticipated, it is extremely difficult to predict the crystal conformation for conformationally flexible molecules. The present study investigates differences in thermodynamic parameters for the free base, c-FB, and an amorphous dihydrochloride salt, a-Di-HCl, of a conformationally flexible drug substance, Tenapanor (RDX5791). A variety of complementary techniques such as, thermal analysis, powder X-ray diffraction (PXRD), and molecular modeling were used to assess the thermodynamic properties and the propensity of crystallization for a-FB and a-Di-HCl, Tenapanor. Molecular modeling and total scattering measurements suggested that the a-Di-HCl salt exists in an open elongated state with local 1D stacking, which extends only to the first nearest neighbor, while the a-FB shows local stacking extending to the third nearest neighbor. The overall relaxation behavior, which typically is an indicator for physical stability, as measured by modulated temperature differential scanning calorimetry and PXRD suggested a nontypical dual relaxation process for the dihydrochloride salt form. The first relaxation was fast and occurred on warming from the quench conditions without any thermal annealing, while the second relaxation step followed a more traditional glass relaxation model, exhibiting an infinite relaxation time. Similar analysis for the a-FB suggested a comparatively shorter relaxation time (about 19 days) that results in its rapid crystallization. This observation is further validated with the extensive amount of physical stability data collected for the a-Di-HCl salt form of Tenapanor under accelerated and stress stability conditions, as well as long-term storage for more than 3 years that show no change in its amorphous state.
Effect of Food Intake on the Pharmacodynamics of Tenapanor: A Phase 1 Study
Clin Pharmacol Drug Dev 2017 Sep;6(5):457-465.PMID:28339149DOI:10.1002/cpdd.341.
Tenapanor (RDX5791/AZD1722) is a minimally systemic small-molecule inhibitor of the sodium/hydrogen exchanger NHE3. Tenapanor acts in the gut to reduce absorption of sodium and phosphate. This phase 1 open-label, 3-way crossover study (NCT02226783) evaluated the effect of food on the pharmacodynamics of Tenapanor. Eighteen volunteers completed a randomized sequence of three 4-day treatments with Tenapanor hydrochloride 15 mg twice daily: before food, after food, and while fasting. Participants received a diet standardized for sodium content. Stool sodium was significantly higher with Tenapanor administration before versus after food (difference, +8.8 mmol/day, P = .006) or while fasting (+11.8 mmol/day, P = .0004). Differences in urinary sodium were not significant. Stool phosphorus was not significantly different with Tenapanor before versus after food and significantly higher before food versus while fasting (+4.9 mmol/day, P = .006). Urinary phosphorus was significantly lower when Tenapanor was administered before (-3.9 mmol/day, P = .0005) or after food (-3.7 mmol/day, P = .0009) versus while fasting. No serious adverse events were reported. These data suggest the effect of Tenapanor on sodium absorption is most pronounced when administered before meals, whereas the effect on phosphate is similar whether administered before or after meals. This may support different timings of Tenapanor administration with respect to food for sodium- and phosphate-related indications.
Elucidating an Amorphous Form Stabilization Mechanism for Tenapanor hydrochloride: Crystal Structure Analysis Using X-ray Diffraction, NMR Crystallography, and Molecular Modeling
Mol Pharm 2018 Apr 2;15(4):1476-1487.PMID:29490140DOI:10.1021/acs.molpharmaceut.7b01047.
By the combined use of powder and single-crystal X-ray diffraction, solid-state NMR, and molecular modeling, the crystal structures of two systems containing the unusually large Tenapanor drug molecule have been determined: the free form, ANHY, and a dihydrochloride salt form, 2HCl. Dynamic nuclear polarization (DNP) assisted solid-state NMR (SSNMR) crystallography investigations were found essential for the final assignment and were used to validate the crystal structure of ANHY. From a structural informatics analysis of ANHY and 2HCl, conformational ring differences in one part of the molecule were observed which influence the relative orientation of a methyl group on a ring nitrogen and thereby impact the crystallizability of the dihydrochloride salt. From quantum chemistry calculations, the dynamics between different ring conformations in Tenapanor is predicted to be fast. Addition of HCl to Tenapanor results in general in a mixture of protonated ring conformers and hence a statistical mix of diastereoisomers which builds up the amorphous form, a-2HCl. This was qualitatively verified by 13C CP/MAS NMR investigations of the amorphous form. Thus, to form any significant amount of the crystalline material 2HCl, which originates from the minor (i.e., energetically less stable) ring conformations, one needs to involve nitrogen deprotonation to allow exchange between the minor and major conformations of ANHY in solution. Thus, by controlling the solution pH value to well below the p Ka of ANHY, the equilibrium between ANHY and 2HCl can be controlled and by this mechanism the crystallization of 2HCl can be avoided and the amorphous form of the dichloride salt can therefore be stabilized.
Preclinical and Healthy Volunteer Studies of Potential Drug-Drug Interactions Between Tenapanor and Phosphate Binders
Clin Pharmacol Drug Dev 2017 Sep;6(5):448-456.PMID:27654985DOI:10.1002/cpdd.307.
Tenapanor (RDX5791, AZD1722), a first-in-class small molecule with minimal systemic availability, is an inhibitor of the sodium/hydrogen exchanger isoform 3. Tenapanor acts locally in the gut, where it reduces absorption of sodium and phosphate. It is being studied in patients with chronic kidney disease requiring dialysis, who are often administered phosphate binders such as sevelamer to help control hyperphosphatemia. We investigated whether coadministration of Tenapanor with phosphate binders (sevelamer or calcium-based binders) impacts the pharmacodynamic effects of Tenapanor. In vitro studies suggested a binding interaction between Tenapanor and sevelamer, but this did not translate into altered pharmacodynamic effects in rats. An open-label, 2-way crossover study was then conducted in healthy volunteers (NCT02346890). This showed that 4 days' treatment with Tenapanor hydrochloride (15 mg twice daily) with or without sevelamer carbonate (800 mg 3 times daily) resulted in comparable 24-hour stool and urinary sodium and phosphorus levels. Stool frequency, consistency, and weight were also comparable between the treatments. These results suggest that the binding between sevelamer and Tenapanor observed in vitro does not translate into altered pharmacodynamic effects in humans.