WO2021115272A1 - 钙敏感受体激动剂化合物及其应用 - Google Patents

钙敏感受体激动剂化合物及其应用 Download PDF

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Publication number
WO2021115272A1
WO2021115272A1 PCT/CN2020/134598 CN2020134598W WO2021115272A1 WO 2021115272 A1 WO2021115272 A1 WO 2021115272A1 CN 2020134598 W CN2020134598 W CN 2020134598W WO 2021115272 A1 WO2021115272 A1 WO 2021115272A1
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Prior art keywords
peptide
arg
compound
conjugating group
phe
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PCT/CN2020/134598
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English (en)
French (fr)
Chinese (zh)
Inventor
吴方舟
张瑾
高菲
吴然
廖成
王雷
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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 AU2020399030A priority Critical patent/AU2020399030B2/en
Priority to CA3159744A priority patent/CA3159744A1/en
Priority to CN202080057062.XA priority patent/CN114222578B/zh
Priority to US17/783,233 priority patent/US20230041996A1/en
Priority to MX2022006892A priority patent/MX2022006892A/es
Priority to BR112022011127A priority patent/BR112022011127A2/pt
Priority to JP2022534636A priority patent/JP7796013B2/ja
Priority to KR1020227022472A priority patent/KR20220110789A/ko
Priority to CN202410744948.1A priority patent/CN118496313A/zh
Priority to EP20899484.8A priority patent/EP4091623A4/en
Publication of WO2021115272A1 publication Critical patent/WO2021115272A1/zh
Anticipated expiration legal-status Critical
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • 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
    • 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
    • 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
    • A61P5/20—Drugs for disorders of the endocrine system of the parathyroid hormones for decreasing, blocking or antagonising the activity of PTH
    • 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 present disclosure belongs to the field of biomedicine, and specifically relates to a compound having an agonist effect on the human calcium sensitive receptor (CaSR), a pharmaceutically acceptable salt thereof, a composition containing the same, and its use in metabolic diseases such as primary Application in the treatment of related metabolic diseases such as hyperparathyroidism, secondary hyperparathyroidism and hypercalcemia.
  • CaSR human calcium sensitive receptor
  • Secondary hyperparathyroidism refers to chronic renal insufficiency, intestinal malabsorption syndrome, Fanconi syndrome and renal tubular acidosis, vitamin D deficiency or resistance, and pregnancy, lactation, etc., the long-term low parathyroid glands
  • Long-term parathyroid hyperplasia eventually leads to the formation of functionally autonomous adenomas.
  • Calsium-sensing receptor refers to a family A G-protein coupled receptor (G-Protein Coupled Receptor, GPCR) distributed on the surface of human parathyroid organ cells.
  • GPCR G-Protein Coupled Receptor
  • the secretion of parathyroid hormone is highly regulated by calcium-sensitive receptors on the surface of parathyroid cells to maintain the steady-state level of human minerals.
  • the calcium-sensitive receptors continuously monitor the subtle changes in the body's calcium ion concentration and then change the parathyroid hormone. The level of secretion responds accordingly.
  • parathyroid hormone In patients with chronic kidney disease, the body's need to achieve steady-state levels of calcium ions and phosphorus ions results in the continuous secretion of parathyroid hormone from the parathyroid glands.
  • This continuous secretion of parathyroid hormone is adaptive at first, but with the progress of chronic kidney disease, it eventually leads to the hyperplasia of parathyroid glands and excessive levels of parathyroid hormone in the body and induces secondary parathyroidism. The formation of hyperthyroidism. Studies have shown that continued secondary hyperparathyroidism can lead to the loss of calcium-sensitive receptors and vitamin D receptors on the surface of parathyroid cells. These downstream pathological effects caused by the disease further lead to the imbalance of the parathyroid gland's regulation of mineral homeostasis in the body.
  • Calcimimetic generally refers to a compound whose physiological function and mechanism of action are similar to calcium ions and can directly activate calcium-sensitive receptors on the surface of parathyroid cells.
  • Cinacalcet hydrochloride is an organic small molecule calcimimetic developed by Amgen. It can activate calcium-sensitive receptors on the surface of parathyroid organs, inhibit the secretion of parathyroid hormone, and achieve the treatment of secondary thyroid. The purpose of related metabolic diseases such as hyperparathyroidism. Cinacalcet hydrochloride is clinically approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. Patients are administered orally. The frequency of use is one to two times a day, with the highest dose It can be 90 mg each time.
  • Cinacalcet hydrochloride shows an excellent clinical effect in reducing plasma parathyroid hormone levels in patients with secondary hyperparathyroidism.
  • significant drug-induced side effects such as nausea, vomiting, and diarrhea related to gastrointestinal side effects, have been observed during patient use.
  • the oral administration of cinacalcet hydrochloride is a larger burden for patients with chronic kidney disease on dialysis, and cinacalcet hydrochloride has been shown to inhibit cytochrome 450 and induce related effects. The interaction between the drug and the drug.
  • a calcium-sensitive receptor agonist compound that can be administered by intravenous injection, which can reduce the secretion of parathyroid hormone by activating the calcium-sensitive receptor on the surface of parathyroid cells to achieve the treatment of secondary parathyroid glands.
  • the efficacy of related metabolic diseases such as hyperfunction.
  • Such calcium-sensitive receptor agonist compounds can significantly improve the treatment compliance and compliance of patients with chronic kidney disease.
  • the purpose of the present disclosure is to provide a compound or a pharmaceutically acceptable salt thereof, which is composed of a peptide and a conjugating group, wherein the peptide is composed of an amino acid sequence represented by the following formula (I):
  • X 1 is D-Cys
  • X 2 is selected from D-Phg, D-Phe(4-CH 3 ), D-Phe(2-Cl), D-Tyr, D-Trp, D-Ser, D-Arg, D-Trp or D-His ;
  • X 3 is D-Arg
  • X 4 is selected from D-Arg, D-Phg, D-Phe (4-CH 3 ), D-2-Thi, D-Phe (4-NO 2 ), D-2-NaI, D-hPhe, D- Abu, D-Tle, D-hLeu, D-Cha, D-Ser, D-Gln, D-Tyr, D-Ile, D-Ser, D-His, D-Val or D-Chg;
  • X 5 is D-Arg
  • X 6 is selected from D-Ala, D-Abu, D-Ser or Gly;
  • X 7 is D-Arg
  • the peptide and the conjugating group are covalently connected through a disulfide bond; wherein the conjugating group is L-Cys, and the residue of X 1 of the peptide is conjugated to the conjugate through a disulfide bond Groups are covalently connected;
  • N-terminal X 1 of the peptide is an acetylation modification and the C-terminal X 7 of the peptide is an amidation modification.
  • X 1 is D-Cys
  • X 2 is selected from D-Phg, D-Phe(4-CH 3 ), D-Phe(2-Cl), D-Tyr, D-Trp, D-Ser or D-His;
  • X 3 is D-Arg
  • X 4 is D-Arg
  • X 5 is D-Arg
  • X 6 is selected from D-Ala, D-Abu, D-Ser or Gly;
  • X 7 is D-Arg
  • conjugating group is L-Cys, and the residue of X 1 of the peptide is covalently connected to the conjugating group through a disulfide bond;
  • N-terminal X 1 of the peptide is an acetylation modification and the C-terminal X 7 of the peptide is an amidation modification.
  • X 1 is D-Cys
  • X 2 is D-Arg
  • X 3 is D-Arg
  • X 4 is selected from D-Arg, D-Phg, D-Phe (4-CH 3 ), D-2-Thi, D-Phe (4-NO 2 ), D-2-NaI, D-hPhe, D- Abu, D-Tle, D-hLeu, D-Chg, D-Ser, D-Cha, D-Gln, D-Tyr, D-His or D-Val;
  • X 5 is D-Arg
  • X 6 is selected from D-Ala, D-Abu, D-Ser or Gly;
  • X 7 is D-Arg
  • conjugating group is L-Cys, and the X 1 residue of the peptide is connected to the conjugating group through a disulfide bond;
  • N-terminal X 1 of the peptide is an acetylation modification and the C-terminal X 7 of the peptide is an amidation modification.
  • X 1 is D-Cys
  • X 2 is D-Arg
  • X 3 is D-Arg
  • X 4 is selected from D-Phg, D-Phe (4-CH 3 ), D-2-Thi, D-Phe (4-NO 2 ), D-2NaI, D-hPhe, D-Abu, D-Tle, D-hLeu, D-Chg, D-Ser, D-Cha, D-Gln, D-Tyr, D-Ile, D-His or D-Val;
  • X 5 is D-Arg
  • X 6 is selected from D-Ala, D-Abu, D-Ser or Gly;
  • X 7 is D-Arg
  • conjugating group is L-Cys, and the X 1 residue of the peptide is connected to the conjugating group through a disulfide bond;
  • N-terminal X 1 of the peptide is an acetylation modification and the C-terminal X 7 of the peptide is an amidation modification.
  • X 1 is D-Cys
  • X 2 is selected from D-Arg
  • X 3 is D-Arg
  • X 4 is selected from D-Phe(4-CH 3 ), D-2-Thi, D-Abu, D-hLeu or D-Val;
  • X 5 is D-Arg
  • X 6 is selected from D-Ala or D-Ser
  • X 7 is D-Arg
  • conjugating group is L-Cys, and the residue of X 1 of the peptide is covalently connected to the conjugating group through a disulfide bond;
  • N-terminal X 1 of the peptide is an acetylation modification and the C-terminal X 7 of the peptide is an amidation modification.
  • X 4 is selected from D-Abu or D-Val; and in other embodiments, X 4 is selected from D-Abu.
  • the present disclosure also relates to a compound having the general formula (II) or a pharmaceutically acceptable salt thereof, the two ends of which are connected in the following manner:
  • R1 is H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, D-pGlu or L-pGlu;
  • R2 is -NH 2 or -OH
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 are as defined in the aforementioned general formula (I).
  • R1 is selected from acetyl group
  • X 1 is selected from the amino acid residue of D-Cys
  • X 2 is selected from D-Phg, D-Phe(4-CH 3 ), D-Phe(2-Cl), D -Tyr, D-Trp, D-Ser, D-Arg or D-His amino acid residue
  • X 3 is selected from D-Arg amino acid residue
  • X 4 is selected from D-Arg, D-Phg, D-Phe (4-CH 3 ), D-2-Thi, D-Phe(4-NO 2 ), D-2-NaI, D-hPhe, D-Abu, D-Tle, D-hLeu, D-Cha, D -Ser, D-Gln, D-Tyr, D-Ile, D-Ser, D-His, D-Val or D-Chg;
  • X 5 is selected from the amino acid residue of D-Arg;
  • X 6 is selected from D-
  • the compound having the general formula (II) or a pharmaceutically acceptable salt thereof wherein said R1 is selected from acetyl group, X1 is selected from amino acid residues of D-Cys; X2 is selected from D-Phg , D-Phe(4-CH 3 ), D-Phe(2-Cl), D-Tyr, D-Trp, D-Ser or D-His amino acid residues; X3 is selected from D-Arg amino acid residues X4 is selected from amino acid residues of D-Arg; X5 is selected from amino acid residues of D-Arg; X6 is selected from amino acid residues of D-Ala, D-Abu, D-Ser or Gly; X7 is selected from D-Arg R2 is selected from -NH2.
  • the compound having the general formula (II) or a pharmaceutically acceptable salt thereof wherein R1 is selected from an acetyl group, X 1 is selected from D-Cys amino acid residues; X 2 is selected from D -Arg amino acid residue; X 3 is selected from D-Arg amino acid residue; X 4 is selected from D-Arg, D-Phg, D-Phe (4-CH 3 ), D-2-Thi, D-Phe (4-NO 2 ), D-2NaI, D-hPhe, D-Abu, D-Tle, D-hLeu, D-Chg, D-Ser, D-Cha, D-Gln, D-Tyr, D-His Or amino acid residues of D-Val; X 5 is selected from amino acid residues of D-Arg; X 6 is selected from amino acid residues of D-Ala, D-Abu, D-Ser or Gly; X 7 is selected from D-Arg R2 is selected from -NH 2
  • the compound having the general formula (II) or a pharmaceutically acceptable salt thereof wherein R1 is selected from an acetyl group, X 1 is selected from D-Cys amino acid residues; X 2 is selected from D -Arg amino acid residue; X 3 is selected from D-Arg amino acid residue; X 4 is selected from D-Phg, D-Phe (4-CH 3 ), D-2-Thi, D-Phe (4-NO 2 ), D-2NaI, D-hPhe, D-Abu, D-Tle, D-hLeu, D-Chg, D-Ser, D-Cha, D-Gln, D-Tyr, D-Ile, D-His Or amino acid residues of D-Val; X 5 is selected from amino acid residues of D-Arg; X 6 is selected from amino acid residues of D-Ala, D-Abu, D-Ser or Gly; X 7 is selected from D-Arg R2 is selected from -NH 2
  • the compound having the general formula (I) or (II) or a pharmaceutically acceptable salt thereof is characterized in that when X 1 is selected from the amino acid residue of D-Cys, it passes through the side chain disulfide The bond connects the residue of X 1 to the second thiol group.
  • the compound or a pharmaceutically acceptable salt thereof is selected from the following compounds:
  • Ac-c(C) means that the amino-terminal cysteine (c) of the D configuration is acetylated, and through a disulfide bond with the other cysteine of the L configuration (C) Acid linkage;
  • r-NH 2 means that the D configuration arginine (r) at the carboxyl terminal is amidated.
  • the present disclosure also relates to a pharmaceutical composition containing any of the foregoing compounds or a pharmaceutically acceptable salt thereof, the composition further containing a pharmaceutically acceptable carrier.
  • the present disclosure also relates to any of the foregoing compounds or their pharmaceutically acceptable salts, and their compositions in preparation for use in reducing the level of parathyroid hormone in a subject, and treating secondary hyperparathyroidism or tumor-induced hypercalcemia Use in medicines.
  • polypeptide compounds provided in the present disclosure belong to amphoteric compounds, and those skilled in the art can use acidic or basic compounds to react with them to form salts through well-known techniques.
  • the pharmaceutical composition containing the polypeptide compound of the present disclosure can be used for the treatment of patients in need of such treatment by way of parenteral administration.
  • Parenteral administration can choose subcutaneous injection, intramuscular injection or intravenous injection.
  • the polypeptide compounds of the present disclosure can also be administered via a transdermal route, such as scalp via a patch, iontophoresis patch; or via a transmucosal route.
  • transdermal route such as scalp via a patch, iontophoresis patch; or via a transmucosal route.
  • Such pharmaceutical compositions and their preparation methods are well known in the art, and the preferred route of administration is intravenous injection.
  • the polypeptide compound provided by the present disclosure is prepared by solid-phase synthesis, the synthesis carrier is Rink-amide-MBHA resin (Xi’an Lanxiao Technology), and the ⁇ -amino group of the amino acid derivative used in the synthesis process is composed of the Fmoc group (fluorenyl Carbonyl) protection, the side chain of amino acid selects the following protecting groups according to the different functional groups: cysteine side chain sulfhydryl group, glutamine side chain amino group, histidine side chain imidazole group is protected by Trt (trityl), The arginine side chain guanidine group is protected by Pbf (2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl), and the tryptophan side chain indolyl group is protected by Boc (tert-butoxy Carbonyl) protection, tyrosine side chain phenol group and serine side chain hydroxyl group are protected by t-Bu (tert-butyl).
  • the carboxyl group of the C-terminal amino acid residue of the polypeptide is first condensed to the polymer insoluble Rink-amide MBHA resin in the form of an amide bond, and then used with 25% 4-methylpiperidine nitrogen, nitrogen-dimethyl
  • the formamide (DMF) solution removes the Fmoc protecting group on the ⁇ -amino group, and then the solid-phase carrier and the next amino acid derivative in the sequence are condensed in excess to form an amide bond to extend the peptide chain.
  • the crude polypeptide solid product is dissolved in a mixed solution of acetonitrile/water containing 0.1% trifluoroacetic acid and purified and separated by a C-18 reverse phase preparative chromatographic column to obtain the pure product of the polypeptide compound.
  • amino acids in the D configuration are expressed as the suffix "D-" before the standard three-letter.
  • D-Ser or represented by the corresponding lowercase single letter, such as s
  • the amino acid in the L configuration is represented by the suffix "L-" in front of the standard three-letter letter, such as L-Cys, or represented by the corresponding uppercase single letter , Such as C
  • glycine has no chirality and is represented by "Gly", or by the corresponding single capital letter "G”.
  • agonist is defined as a substance that activates the type of receptor in question.
  • calcium-sensitive receptor agonist used in the context of the present disclosure refers to a substance or ligand that can activate calcium-sensitive receptors.
  • treatment includes inhibiting, slowing down, stopping or reversing the existing symptoms or the progression or severity of the patient.
  • the parathyroid hormone used in the present disclosure is an 84 amino acid peptide produced by the parathyroid gland and its breakdown product. In addition to the full-length parathyroid hormone, there are various parathyroid hormone fragments produced by proteolysis and other metabolic pathways in the blood. The region 1-34 at the amino terminus of the complete parathyroid hormone molecule is biologically active. Different methods for measuring the level of parathyroid hormone have been developed in the industry and are known in the art.
  • “Naturally-occurring amino acids” refers to 20 kinds of naturally-occurring conventional amino acids (ie alanine (Ala, A), cysteine (Cys, C), aspartic acid (Asp, D), glutamic acid ( Glu, E), phenylalanine (Phe, F), glycine (Gly, G), histidine (His, H), isoleucine (Ile, I), lysine (Lys, K), Leucine (Leu, L), Methionine (Met, M), Asparagine (Asn, N), Proline (Pro, P), Glutamine (Gln, Q), Arginine ( Arg, R), serine (Ser, S), threonine (Thr, T), valine (Val, V), tryptophan (Trp, W) and tyrosine (Tyr, Y).
  • conventional amino acids ie alanine (Ala, A), cysteine (Cys
  • Non-naturally occurring amino acids refer to amino acids that are not naturally encoded or found in the genetic code of any organism. They can be, for example, purely synthetic compounds. Examples include, but are not limited to, D-2-aminobutyric acid (D-Abu), 3-cyclohexyl-D-alanine (D-Cha), 3-(2-thienyl)-D-alanine ( D-2-Thi), 2-naphthyl-D-alanine (D-2-NaI), D-phenylglycine (D-Phg), D-2-chlorophenylalanine (D-Phe( 2-Cl)), D-4-nitrophenylalanine (D-Phe(4-NO 2 )), D-4-methylphenylalanine (D-Phe(4-Me)), D -Homophenylalanine (D-hPhe), D-tert-leucine (D-Tle), D-homoleucine (D-hLeu),
  • the C-terminal carboxyl group, the N-terminal amino group and/or the side chain functional group of the natural amino acid or the unnatural amino acid are chemically modified.
  • X is selected from A, B, or C
  • X is selected from A, B and C
  • X is A, B or C
  • X is A, B and C
  • other terms all express the same Meaning, which means that X can be any one or more of A, B, and C.
  • the hydrogen atoms described in the present disclosure can be replaced by its isotope deuterium, and any hydrogen atom in the embodiment compounds involved in the present disclosure can also be replaced by a deuterium atom.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but does not have to be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the biological body and facilitate the absorption of the active ingredient to exert its biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present disclosure, which is safe and effective when used in mammals, and has due biological activity.
  • the subject as used herein refers to a human subject or an animal subject.
  • sulfhydryl-containing groups or sulfhydryl-containing moieties herein refer to functional groups that contain sulfur-hydrogen bonds and can form disulfide bonds with another sulfhydryl group under physiological conditions.
  • Figure 1 shows the hemolytic effects of Example Compounds 12, 13, 17, 19, 29, 31 against human red blood cells in vitro, *: positive control (polyethylene glycol octyl phenyl ether), #: PBS buffer.
  • Figure 2 shows the efficacy of 3 mg/kg Example Compounds 13, 17, 31 and Etekatide (AMG-416) in reducing the level of parathyroid hormone in normal rats.
  • Figure 3 shows the efficacy of 3 mg/kg of Example Compounds 13, 17, 31 and Etecatide (AMG-416) in reducing serum calcium ion levels in normal rats.
  • Figure 4 shows the efficacy of Example Compound 17 and Etekatide (AMG-416) in reducing the level of parathyroid hormone in 5/6 nephrectomy rats.
  • Figure 5 shows the efficacy of Example Compound 17 and Etekatide (AMG-416) in reducing serum calcium ion levels in 5/6 nephrectomy rats.
  • the Fmoc/tBu synthesis strategy was used for solid-phase peptide synthesis on the Prelude-X automatic peptide synthesizer, starting from Rink-amide MBHA resin (0.1mmole), which used 10 equivalents of HCTU and 4-methylmorpholine activated Amino acid residues (the molar ratio of HCTU, 4-methylmorpholine and amino acid residues are 1:2:1) are coupled in nitrogen, nitrogen-dimethylformamide at room temperature for 25 minutes.
  • the cleavage of the peptide from the solid phase resin, the removal of the side chain protecting group and the activation of the D-Cys side chain sulfhydryl group were completed at the same time in 2 hours at room temperature.
  • the resin was filtered and washed twice with trifluoroacetic acid. After the filtrate was combined, a large amount of frozen methyl tert-butyl ether was added to precipitate solids. After centrifugation, the supernatant was removed to obtain the crude polypeptide and dried and weighed.
  • the mixture obtained above was filtered through a 0.22um membrane and separated by a WATERS Prep150 preparative reversed-phase high performance liquid chromatography system.
  • the buffers were A (0.1% trifluoroacetic acid, aqueous solution) and B (0.1% trifluoroacetic acid, 90 % Acetonitrile, aqueous solution).
  • the preparative chromatographic column is an X-SELECT OBD C-18 (WATERS) reversed-phase chromatographic column.
  • the detection wavelength of the chromatograph is set to 220 nm, and the flow rate is 15 mL/min.
  • the relevant fractions of the product were collected and lyophilized to obtain the pure polypeptide of Example No.
  • the purity and compound identity of the pure polypeptides are determined by analytical ultra-high performance liquid chromatography and ultra-high performance liquid chromatography/mass spectrometry.
  • the purity of the compound is 96.78%, and the molecular weight of the compound is 1109.60.
  • the purpose of this test example is to measure the agonist activity of compound 1-38 on the human calcium sensitive receptor (CaSR).
  • the HEK293/CaSR stably transfected cell line (source: Kanglong Chemicals) was cultured in complete medium (ingredients: DMEM, high glucose+10% FBS+2mM GlutaMAX+1X Penicillin-Streptomycin+200 ⁇ g/ml Hygromycin B) at 37°C , Incubate in a 5% CO 2 environment to 70%-90% fusion.
  • the cell line was digested with TrypLE and then seeded on a 384-well cell culture plate, and cultured overnight at 37°C and 5% CO 2.
  • the EnVision detector was used to read the signal of HTRF, the excitation wavelength was 320nm, and the emission wavelengths were 620nm and 665nm. Calculate the signal ratio (665nm/620nm*10,000), and use a four-parameter equation to perform nonlinear fitting between the signal ratio and the sample concentration in GraphPad Prism 6 to obtain the EC 50 value of the test example 1-38, see for specific values Table 2 below.
  • a considerable part of the embodiments of the present disclosure have excellent in vitro efficacy, corresponding to an EC50 value of less than 10 uM in the evaluation of human calcium-sensing receptor agonist activity in vitro.
  • rat peritoneal mast cells were separated by lavage of rat peritoneum with lavage buffer (cold HBSS containing heparin 5 U/mL + 25 mM HEPES, pH 7.4). After separation, the cells were centrifuged, the lavage buffer was removed, and the stimulation buffer (HBSS+25mM HEPES+1mM CaCl 2 , pH 7.4) was added to resuspend the cells and washed twice.
  • lavage buffer cold HBSS containing heparin 5 U/mL + 25 mM HEPES, pH 7.4
  • SPF-grade normal adult rats (Sprague Dawley, SD), weighing 250-350 grams, were used in the animal room to recover from a normal diet for 7 days.
  • the rats were randomly divided into groups, 6 in each group, half male and half male, and numbered separately.
  • the 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 value before administration.
  • the plasma separation method is to use K2-EDTA anticoagulation, collect blood through the jugular vein, place it on ice after collection, and then centrifuge the whole blood at 6,800rpm for 6 minutes at 2 ⁇ 8°C, and gently take out the upper layer, which is the plasma.
  • the method of serum separation is to collect blood through the jugular vein, let the whole blood stand at room temperature for 1 hour, then centrifuge at 3,500 rpm for 10 minutes at room temperature, gently remove the upper layer, which is the serum, and store it at room temperature. Beginning the day before the experiment, the animals were fasted overnight and had free drinking water. On the next day after blood collection, Example Compounds 13, 17, 31 and Etecartide (AMG-416) were dissolved in Phosphate Buffered Saline (PBS, Gibco), and each rat was given Example Compound 13 by intravenous injection.
  • PBS Phosphate Buffered Saline
  • the reaction strip is sealed with a sealing film, and the reaction strip is wrapped with aluminum foil for storage in the dark.
  • it is shaken on a horizontal shaker at a rotation speed of 180-220 rpm for 30 minutes.
  • the absorbance of each well was read at 450 nm, and the absorbance at 620 nm was used as 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.
  • Draw a standard curve based on the absorbance of the standard, and then combine the absorbance of other samples with the standard curve to calculate the actual plasma concentration of parathyroid hormone.
  • the determination of serum calcium ion concentration is carried out according to the steps of the relevant kit.
  • the rats were adaptively fed, under anesthesia, 2/3 of the left kidney was surgically removed, and after one week of recovery, the right kidney was surgically removed to establish a 5/6 nephrectomy rat model.
  • the animals were bred normally for 2 weeks, and the levels of creatinine (CREA) and plasma parathyroid hormone were detected. According to the levels of parathyroid hormone, they were randomly divided into 4 groups, including the normal saline group, the compound 17 low-dose group, and the compound 17 high-dose group and etacatide group, 10 rats in each group.
  • the normal saline group, the compound 17 low-dose group, the compound 17 high-dose group and the etecartide group were given normal saline, 1 mg/kg compound 17, 2 mg/kg compound 17 and 1 mg/kg iteca through the tail vein, respectively.
  • the peptide was administered once a day for 28 consecutive days. During the administration period, the animal body weight, plasma parathyroid hormone level, serum calcium ion and other indicators were measured. The first day of administration after the animals were grouped was recorded as the first day of the experiment.
  • compound example 17 1mg/kg and 2mg/kg can dose-dependently reduce the plasma parathyroid hormone level in rats.
  • each administration group is It can reduce the parathyroid hormone to a very low level. From the 14th day, the parathyroid hormone decreases by more than 90%.
  • 1 mg/kg compound 17 inhibited the plasma parathyroid hormone level at 6h and 16h after administration slightly better or comparable to the same dose of etecartide ( Figure 4). Decreased blood calcium is a mechanism-related effect of this class of drugs.

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CN202080057062.XA CN114222578B (zh) 2019-12-09 2020-12-08 钙敏感受体激动剂化合物及其应用
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MX2022006892A MX2022006892A (es) 2019-12-09 2020-12-08 Compuesto agonista del receptor sensor de calcio y aplicación del mismo.
BR112022011127A BR112022011127A2 (pt) 2019-12-09 2020-12-08 Composto agonista do receptor de detecção de cálcio e aplicação do mesmo
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