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WO2022257940A1 - Sel chlorhydrate d'un composé agoniste du récepteur de détection du calcium, composition pharmaceutique et utilisation de celui-ci - Google Patents

Sel chlorhydrate d'un composé agoniste du récepteur de détection du calcium, composition pharmaceutique et utilisation de celui-ci Download PDF

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Publication number
WO2022257940A1
WO2022257940A1 PCT/CN2022/097489 CN2022097489W WO2022257940A1 WO 2022257940 A1 WO2022257940 A1 WO 2022257940A1 CN 2022097489 W CN2022097489 W CN 2022097489W WO 2022257940 A1 WO2022257940 A1 WO 2022257940A1
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WIPO (PCT)
Prior art keywords
compound
calcium
formula
hydrochloride salt
hydrochloride
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PCT/CN2022/097489
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English (en)
Chinese (zh)
Inventor
侯大龙
孔祥林
齐艳艳
彭政
高俊
林凡城
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Beijing Tuo Jie Biopharmaceutical Co Ltd
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Beijing Tuo Jie Biopharmaceutical Co Ltd
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Priority to CN202280040463.3A priority Critical patent/CN117500820A/zh
Publication of WO2022257940A1 publication Critical patent/WO2022257940A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids

Definitions

  • the disclosure belongs to the field of medical technology, and in particular relates to a hydrochloride salt of a compound having an agonist effect on human calcium-sensing receptors (CaSR), its composition and its application, and can be used for metabolic diseases such as primary parathyroid Treatment of hyperthyroidism, secondary hyperparathyroidism and hypercalcemia and other related metabolic diseases.
  • CaSR human calcium-sensing receptors
  • CaSR Calcium-sensing Receptor
  • GPCR G-Protein Coupled Receptor
  • parathyroid hormone In patients with chronic kidney disease, the need to achieve steady-state levels of calcium and phosphate ions results in a continuous secretion of parathyroid hormone from the parathyroid glands. This continuous secretion of parathyroid hormone is initially adaptive, but as chronic kidney disease progresses it eventually leads to parathyroid hyperplasia and excessive parathyroid hormone levels in the body and induces secondary parathyroid hormone The formation of hyperthyroidism. Studies have shown that persistent secondary hyperparathyroidism leads to the loss of calcium-sensing receptors and vitamin D receptors on the surface of parathyroid cells. These disease-induced downstream pathological effects further contribute to the dysregulation of parathyroid regulation of mineral homeostasis in the body.
  • Calcimimetic generally refers to compounds whose physiological function and mechanism of action are similar to calcium ions and can directly activate calcium-sensing receptors on the surface of parathyroid cells.
  • Cinacalcet hydrochloride is an organic small-molecule calcimimetic agent developed by Amgen, which can activate the calcium-sensing receptor on the surface of the parathyroid organ, inhibit the secretion level of parathyroid hormone and achieve the treatment of secondary parathyroid glands. Hyperfunction and other related metabolic diseases. Cinacalcet hydrochloride is clinically approved for the treatment of secondary hyperparathyroidism in dialysis patients with chronic kidney disease. Patients are administered orally, and the frequency of use is once or twice a day. The maximum dose can be 90 mg each time.
  • Cinacalcet hydrochloride has clinically demonstrated excellent efficacy in reducing plasma parathyroid hormone levels in patients with secondary hyperparathyroidism.
  • significant drug-induced side effects such as nausea, vomiting, and diarrhea associated with gastrointestinal side effects, were observed during patient use.
  • the oral administration of cinacalcet hydrochloride is a greater burden for chronic kidney disease patients on dialysis, and cinacalcet hydrochloride has been shown to inhibit cytochrome 450 and induce drug-drug interaction between.
  • calcium-sensing receptor agonist compounds that can be administered by intravenous injection, which can reduce the secretion of parathyroid hormone by activating the calcium-sensing receptor on the surface of parathyroid gland cells, thereby achieving the treatment of secondary parathyroid Hyperthyroidism and other related metabolic diseases.
  • Such calcium-sensing receptor agonist compounds can significantly improve the compliance and compliance of patients with chronic kidney disease.
  • WO2021115272 describes a series of polypeptide calcium-sensing receptor agonist compounds, wherein the compound of formula (I) has an agonist effect on human calcium-sensing receptors to reduce plasma parathyroid hormone and serum calcium ion levels, and can be used for secondary Treatment of metabolic diseases such as hyperparathyroidism and tumor-induced hypercalcemia.
  • the present disclosure provides a hydrochloride salt of a calcium-sensing receptor agonist, a pharmaceutical composition and application thereof.
  • the hydrochloride salt of the compound provided by the disclosure has high solubility and high stability, not only can effectively reduce plasma parathyroid hormone, but also has low release level of histamine and few side effects.
  • Amino acid sequences in this disclosure are represented by the standard one-letter or three-letter codes for amino acids, namely alanine (Ala, A), cysteine (Cys, C), arginine (Arg, R), D-2 - Aminobutyric acid (D-Abu).
  • the compound of formula (I) in the present disclosure can also be represented by the following sequence: Ac-c(C)-rr-(D-Abu)-rar-NH 2 .
  • the number of the compound of formula (I) combined with hydrochloric acid in the hydrochloride of the compound of formula (I) can be 1-10 (can be any value between 1-10, that is, the average value), preferably
  • the number of hydrochloric acid is 4-8, more preferably 4-5
  • the optional number of hydrochloric acid includes but not limited to 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 , 8, 8.5, 9, 9.5, 10.
  • the present disclosure provides a use of the hydrochloride of the above-mentioned compound in the preparation of a drug for reducing the level of parathyroid hormone in a subject and treating secondary hyperparathyroidism or tumor-induced hypercalcemia.
  • the present disclosure also provides a hydrochloride of the above-mentioned compound, which is used for reducing the level of parathyroid hormone in a subject and treating secondary hyperparathyroidism or hypercalcemia caused by tumors.
  • the hyperparathyroidism is secondary hyperparathyroidism in a subject suffering from chronic kidney disease.
  • Another aspect of the present disclosure provides a method for preparing the hydrochloride of the above compound, comprising the step of mixing the compound represented by formula (I) with hydrochloric acid.
  • the present disclosure provides a method for preparing the hydrochloride of the above-mentioned compound, which specifically includes: (1) using a resin to sequentially couple 7 amino acids of the main chain and acetic anhydride through solid phase synthesis to obtain a main chain resin peptide; The lysate of H 2 O/TIS/DPDS was stirred and reacted at room temperature to obtain the crude peptide of the main chain; (3) reacted with HL-Cys-OH in aqueous solution to obtain the crude peptide; (4) purified by high pressure preparation and nanofiltration, and concentrated to obtain the finished product .
  • Fig. 1 is the hemolytic effect of the compound of formula (I) on human red blood cells in vitro, wherein *: positive control (polyethylene glycol octylphenyl ether), #: PBS buffer solution;
  • Fig. 2 is the effect that formula (I) compound reduces parathyroid hormone level in normal rat body
  • Fig. 3 is the efficacy of compounds of formula (I) in reducing serum calcium ion levels in normal rats.
  • Solid-phase peptide synthesis was performed using the Fmoc/tBu synthesis strategy on a Prelude-X automated peptide synthesizer, starting from Rink-amide MBHA resin (0.1 mmole) using 10 equivalents of HCTU and 4-methylmorpholine activated Amino acid residues (HCTU, 4-methylmorpholine and amino acid residues in a molar ratio of 1:2:1) were coupled in nitrogen, nitrogen-dimethylformamide at room temperature for 25 minutes.
  • the mixed solution obtained above was filtered through a 0.22um membrane, it was separated with a WATERS Prep150 preparative reversed-phase high-performance liquid chromatography system, and the buffer solution was A (0.1% trifluoroacetic acid, aqueous solution) and B (0.1% trifluoroacetic acid, 90 % acetonitrile, in water).
  • the preparation chromatographic column is X-SELECT OBD C-18 (WATERS) reversed-phase chromatographic column.
  • the detection wavelength of the chromatograph is set at 220nm, and the flow rate is 15mL/min.
  • Ac-c(C) means that the D-configuration cysteine (c) at the amino terminal is acetylated and linked to another cysteine in the L-configuration (C) through a disulfide bond;
  • r-NH 2 means that the D-configuration arginine (r) at the carboxy-terminus is amidated.
  • the compound of formula (I) is synthesized by a synthetic scheme similar to that of Example 1, and the purity and molecular weight of the synthetic polypeptide are determined by analytical ultra-high performance liquid chromatography and ultra-high performance liquid chromatography/mass spectrometry, wherein the purity of the compound of formula (I) is 95.79%, the molecular weight of the compound is: 1062.29Da.
  • the formula (I) compound hydrochloride that embodiment 1 makes is respectively at 40 °C ⁇ 2 °C and RH75% ⁇ 5%, 25 °C and total illumination greater than 1.2 * 106Lux hr, near ultraviolet energy is greater than 200w hr/m 2. Put it under the conditions of 25°C and RH60% for a period of time to investigate its stability. The results are shown in the table below.
  • the HEK293/CaSR stably transfected cell line (source: Pharmaron) was cultured in complete medium (ingredients: DMEM, high glucose+10% FBS+2mM GlutaMAX+1X Penicillin-Streptomycin+200 ⁇ g/ml Hygromycin B), at 37°C , and incubate to 70%-90% confluence in a 5% CO2 environment.
  • the cell lines were digested with TrypLE and inoculated in 384-well cell culture plates, and cultured overnight at 37°C in 5% CO2.
  • the stimulation buffer HEPES 10mM, MgCl2 0.5mM, KCl 4.2mM, NaCl 146mM, glucose 5.5mM, LiCl 50mM, CaCl2 1.2mM
  • the stimulation buffer HEPES 10mM, MgCl2 0.5mM, KCl 4.2mM, NaCl 146mM, glucose 5.5mM, LiCl 50mM, CaCl2 1.2mM
  • different concentrations of the compounds to be tested were added at 37°C. Incubate for 60 minutes, and detect the production of IP-One in the cells according to the steps in the instructions of the Cisbio IP-One Tb kit.
  • software is used to calculate the EC50 value of each example to be tested on human calcium-sensing receptors, and to evaluate the agonist activity of the examples against human calcium-sensing receptors.
  • Signal readout for HTRF was performed using an EnVision detector with excitation at 320 nm and emission at 620 nm and 665 nm. Calculate the signal ratio (665nm/620nm*10,000), and use the four-parameter equation to perform nonlinear fitting between the signal ratio and the sample concentration in GraphPad Prism 6, and obtain the EC50 value of Example 1 to be tested. The specific values are shown in Table 1 below .
  • Example number sequence Calcium Sensing Receptor EC 50 Compound of formula (I) Ac-c(C)-rr-(D-Abu)-rar-NH 2 6.28 Etekatide Ac-c(C)-arrrar-NH 2 6.78 Etekatide analogs Ac-c(C)-rrarar-NH 2 6.74
  • the compound of formula (I) of the present disclosure has excellent in vitro efficacy, corresponding to an EC50 value lower than 10uM in the in vitro evaluation of human calcium-sensing receptor agonist activity, which is equivalent to the activity of the positive drug etekatide.
  • rat peritoneal mast cells were isolated by lavage of rat peritoneum with lavage buffer (cold HBSS+25mM HEPES containing 5 U/mL heparin, pH 7.4). After separation, the cells were centrifuged, the lavage buffer was removed, and the stimulation buffer (HBSS+25mM HEPES+1mM CaCl2, pH 7.4) was added to resuspend the cells and washed twice.
  • lavage buffer cold HBSS+25mM HEPES containing 5 U/mL heparin, pH 7.4
  • Etecartide can obviously cause the release of histamine from rat peritoneal mast cells in vitro, which is specifically reflected in the fact that the relative histamine release multiple is higher than 1.50 relative to PBS buffer.
  • the compound of formula (I) greatly reduces the release level of histamine in rat peritoneal mast cells in vitro compared with etecartide.
  • the erythrocytes were resuspended by the compound solution of the example to be tested, polyethylene glycol octylphenyl ether-100 solution and PBS buffer respectively and incubated at 37° C. for 1 hour. After incubation, centrifuge at 4°C for 10 minutes and extract the supernatant (100ul), transfer to a 96-well plate and measure the absorbance at 540nm to evaluate the hemolytic effect of the compound of formula (I) on red blood cells in vitro.
  • Formula (I) compound does not observe obvious erythrocyte hemolysis effect under the concentration of 100ug/ml, and corresponding polyethylene glycol octyl phenyl ether-100 solution observes obvious erythrocyte hemolysis effect under experimental conditions, see Attached Figure 1.
  • Rats Normal adult rats (Sprague Dawley, SD) of SPF grade were used in the experiment, weighing 250-350 grams, and were restored to normal diet for 7 days in the animal room. Rats were divided into random groups, 6 in each group, half male and half male, and numbered respectively. One day before the start of the experiment, 540 ⁇ L of blood was collected from each rat, and the plasma parathyroid hormone level and serum calcium ion concentration were measured as the control values before administration.
  • the plasma separation method is anticoagulated with K2-EDTA, blood is collected through the jugular vein, put on ice after collection, and then the whole blood is centrifuged at 6,800 rpm for 6 minutes at 2-8°C, and the upper layer is gently taken out to be the plasma, 2 Store at ⁇ 8°C.
  • the serum separation method is to collect blood through the jugular vein, let the whole blood stand at room temperature for 1 hour, then centrifuge at room temperature at 3,500rpm for 10 minutes, gently take out the upper layer, which is the serum, and store it at room temperature. The day before the experiment, the animals were fasted overnight and had free access to water.
  • ELISA Enzyme-linked immunosorbent assay, enzyme-linked immunosorbent assay.
  • the detailed steps are: use the streptavidin pre-coated reaction strip provided by the kit, and add 25 ⁇ L of standard substance, control substance or plasma sample to each well. Mix biotinylated rat parathyroid hormone antibody and rat parathyroid hormone/HRP-conjugated antibody 1:1, and add 100 ⁇ L of this mixed solution to each well. Seal the reaction strips with a sealing film, wrap the reaction strips with aluminum foil for storage in the dark, and oscillate on a horizontal shaker at 220 rpm for 3 h at room temperature.
  • the absorbance of each well was read at 450 nm, and the absorbance at 620 nm was used as the background subtraction.
  • 150 ⁇ L of horseradish peroxidase ELISA substrate plus 100 ⁇ L of ELISA stop solution was used as a blank control for absorbance measurement.
  • the determination of serum calcium ion concentration is carried out according to the steps of the relevant kit.
  • the compound of formula (I) completely reduces the plasma parathyroid hormone level of normal rats within 4 hours at a dose of 3 mg/kg, and the serum calcium ion level is also correspondingly reduced, see accompanying drawings 2 and 3.

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Abstract

L'invention concerne un sel chlorhydrate d'un composé agoniste du récepteur de détection du calcium, une composition pharmaceutique et une utilisation de celui-ci. Plus particulièrement, l'invention concerne un sel chlorhydrate d'un composé agoniste du récepteur de détection du calcium polypeptidique, une composition pharmaceutique et une utilisation de celui-ci. Le sel chlorhydrate a un effet agoniste sur un récepteur de détection du calcium (CaSR) humain de manière à réduire l'hormone parathyroïde plasmatique et le taux d'ions calcium sériques, et peut être utilisé pour le traitement de maladies métaboliques telles que l'hyperparathyroïdisme secondaire et l'hypercalcémie induite par une tumeur.
PCT/CN2022/097489 2021-06-08 2022-06-08 Sel chlorhydrate d'un composé agoniste du récepteur de détection du calcium, composition pharmaceutique et utilisation de celui-ci Ceased WO2022257940A1 (fr)

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CN202280040463.3A CN117500820A (zh) 2021-06-08 2022-06-08 钙敏感受体激动剂化合物的盐酸盐及药物组合物和其应用

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CN202110637105 2021-06-08

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118398157B (zh) * 2024-03-18 2025-03-18 南方医科大学珠江医院 西那卡塞治疗继发性甲状旁腺功能亢进的药效应评估方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107674114A (zh) * 2009-07-29 2018-02-09 凯伊药品公司 用于降低甲状旁腺激素水平的治疗剂
CN109985228A (zh) * 2011-11-10 2019-07-09 凯伊药品公司 拟钙剂及其使用方法
WO2021115272A1 (fr) * 2019-12-09 2021-06-17 北京拓界生物医药科技有限公司 Composé agoniste du récepteur de détection du calcium et son application
WO2022052471A1 (fr) * 2020-09-10 2022-03-17 陕西麦科奥特科技有限公司 Composé polypeptidique de fusion bispécifique

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107674114A (zh) * 2009-07-29 2018-02-09 凯伊药品公司 用于降低甲状旁腺激素水平的治疗剂
CN109985228A (zh) * 2011-11-10 2019-07-09 凯伊药品公司 拟钙剂及其使用方法
WO2021115272A1 (fr) * 2019-12-09 2021-06-17 北京拓界生物医药科技有限公司 Composé agoniste du récepteur de détection du calcium et son application
WO2022052471A1 (fr) * 2020-09-10 2022-03-17 陕西麦科奥特科技有限公司 Composé polypeptidique de fusion bispécifique

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