Pharmaceutical composition for treating or preventing cystic diseases

Abstract

The present invention provides a pharmaceutical composition for treating or preventing cystic diseases and comprising a phosphate transporter inhibiting compound as an active ingredient.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition for treating or preventing cystic diseases, comprising a compound that inhibits phosphate transporters as an active ingredient. The present invention also relates to a method for predicting the sensitivity of a patient with cystic diseases to a selective inhibitor of NaPi-IIb, and a method for treating or preventing cystic diseases. Background Art

[0002] Cystic diseases include cystic kidney disease, pancreatic cystic disease, cystic liver, cystic lung disease, pancreatic cysts, etc.

[0003] As one of the cystic diseases, polycystic kidney disease (PKD) is a hereditary disease in which many cysts form in the kidneys. The growth of the cysts causes an increase in kidney size and a decrease in kidney function (NPL1).

[0004] To date, tolvaptan is the only drug used to treat PKD, but side effects such as hepatotoxicity, polyuria, etc. have been reported (NPL 3). Therefore, it has been desired to develop new PKD treatments to reduce these problems.

[0005] Phosphorus is an element present in each cell and accounts for 1% of body weight, and plays an important role in life support (such as cell energy metabolism). The concentration of phosphorus in the blood is regulated by bone formation and bone resorption, in addition to being absorbed from the gastrointestinal tract and excreted from the kidneys, and is regulated to a constant concentration. Phosphorus absorption in the gastrointestinal tract is mainly performed by NaPi-IIb (SLC34A2) (a phosphate transporter) (NPL 4 and 5). Phosphorus in the blood is filtered in the glomerulus of the kidney, and the required amount is mainly reabsorbed by NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) (NPL 4 and 6) in the renal tubules. Kidney plays a very important role in the regulation of phosphorus in the body, and in end-stage renal failure and dialysis patients with impaired renal function, phosphorus accumulates in the body, thereby causing an increase in blood phosphorus concentration, i.e. hyperphosphatemia.

[0006] Inhibition of NaPi-IIb plays an important role in phosphorus absorption in the gastrointestinal tract and is believed to be able to inhibit phosphorus absorption in the gastrointestinal tract similarly to a phosphorus adsorbent and reduce phosphorus concentration in the blood (NPL 5 and 7). So far, there have been some reports on NaPi-IIb inhibitors (PTL 1 to 6, NPL 8 and 9).

[0007] Citation List

[0008] Patent Literature

[0009] PTL 1: International Publication No. WO2012 / 006475

[0010] PTL 2: International Publication No. WO2011 / 136269

[0011] PTL 3: International Publication No. WO2008 / 051980

[0012] PTL 4: International Publication No. WO2013 / 062065

[0013] PTL 5: International Publication No. WO2016 / 039458

[0014] PTL 6: International Publication No. WO2014 / 142273

[0015] Non-patent literature

[0016] NPL 1: Vervloe, M., Nat Rev Nephrol. 2019 Feb;15(2):70-72

[0017] NPL 2: Wu, M. et al., Kidney Dis 2016;2:128-135

[0018] NPL 3: Blair, HA, et al., Drugs. 2019 Feb;79(3):303-313

[0019] NPL 4: Miyamoto, K. et al., J Pharm Sci. 2011 Sep;100(9):3719-30

[0020] NPL 5: Sabbagh, Y. et al., J Am Soc Nephrol. 2009 Nov;20(11):2348-58

[0021] NPL 6: Murer, H. et al., Pflugers Arch. 2004 Feb;447(5):763-7

[0022] NPL 7: Ohi, A. et al., Am J Physiol Renal Physiol. 2011 Nov;301(5):F1105-13

[0023] NPL 8: Tsuboi, Y., et al., Kidney International (2020) 98, 343-354

[0024] NPL 9: Maruyama, S. et al., Kidney International Reports (2021) 6, 675-684

[0025] NPL 10: Dixon EE., J Am Soc Nephrol. 2022 Feb;33(2):279-289 Summary of the invention

[0026] Technical issues

[0027] One object of the present invention is to provide a medicament for the treatment or prevention of cystic diseases.

[0028] Solution to the problem

[0029] In view of the above problems, the present inventors have conducted research and have found that phosphate transporters are highly expressed in renal tissues of patients with cystic diseases. The present inventors have also found that compounds that inhibit phosphate transporters have excellent effects in treating or preventing cystic diseases, and have completed the present invention. This description covers the following disclosures of the present invention.

[0030] [A-1] A pharmaceutical composition comprising a compound that inhibits phosphate transporters as an active ingredient for use in treating or preventing cystic diseases.

[0031] [A-2] A pharmaceutical composition for inhibiting the formation or expansion of a cyst, the pharmaceutical composition comprising a compound that inhibits a phosphate transporter as an active ingredient.

[0032] [A-3] The pharmaceutical composition according to [A-1] or [A-2], wherein the phosphate transporter is at least one selected from the group consisting of NaPi-IIa, NaPi-IIb, and NaPi-IIc.

[0033] [A-4] The pharmaceutical composition according to any one of [A-1] to [A-3], wherein the phosphate transporter is NaPi-IIb.

[0034] [A-5] The pharmaceutical composition according to any one of [A-1], [A-3] and [A-4], wherein the cystic disease is a disease in which NaPi-IIb is highly expressed in an organ that develops cystic disease.

[0035] [A-6] The pharmaceutical composition according to any one of [A-1] and [A-3] to [A-5], wherein the cystic disease is a disease involving NaPi-IIb.

[0036] [A-7] The pharmaceutical composition according to any one of [A-2] to [A-4], wherein NaPi-IIb is highly expressed in cells of cysts.

[0037] [A-8] The pharmaceutical composition according to any one of [A-2] to [A-4] and [A-7], wherein the cyst is a cyst involving NaPi-IIb.

[0038] [A-9] The pharmaceutical composition according to any one of [A-1] to [A-8], wherein the compound is at least one selected from the group consisting of low molecular weight compounds, polypeptides, and polynucleotides.

[0039] [A-10] The pharmaceutical composition according to any one of [A-1] to [A-9], wherein the compound is a low molecular weight compound having a molecular weight of 2000 g / mol or less.

[0040] [A-11] The pharmaceutical composition according to any one of [A-1] to [A-9], wherein the compound is a low molecular weight compound having a molecular weight of 1000 g / mol or less.

[0041] [A-12] The pharmaceutical composition according to any one of [A-1] to [A-9], wherein the compound is a polypeptide comprising an antibody.

[0042] [A-13] The pharmaceutical composition according to any one of [A-1] to [A-9], wherein the compound is an anti-phosphate transporter antibody.

[0043] [A-14] The pharmaceutical composition according to any one of [A-1] to [A-13], wherein the compound is at least one selected from the group consisting of anti-NaPi-IIa antibodies, anti-NaPi-IIb antibodies, and anti-NaPi-IIc antibodies.

[0044] [A-15] The pharmaceutical composition according to any one of [A-1] to [A-9], wherein the compound is an anti-NaPi-IIb antibody.

[0045] [A-16] The pharmaceutical composition according to any one of [A-1] to [A-9], wherein the compound is a polynucleotide selected from the group consisting of ribozymes, antisense molecules, inhibitor oligonucleotides, aptamers, microRNAs and small interfering RNAs (siRNAs).

[0046] [A-17] The pharmaceutical composition according to any one of [A-1] to [A-9], wherein the compound is a polynucleotide selected from the group consisting of an antisense molecule, a microRNA, and a small interfering RNA (siRNA).

[0047] [A-18] The pharmaceutical composition according to any one of [A-1] to [A-17], wherein the compound is at least one selected from the following (i) to (iii):

[0048] (i) low molecular weight compounds having a molecular weight of 2000 g / mol or less;

[0049] (ii) anti-NaPi-IIb antibodies; and

[0050] (iii) a polynucleotide selected from the group consisting of an antisense molecule, a microRNA, and a small interfering RNA (siRNA).

[0051] [A-19] The pharmaceutical composition according to any one of [A-1] to [A-18], wherein the compound is administered parenterally.

[0052] [A-20] The pharmaceutical composition according to any one of [A-1] to [A-11] and [A-18], wherein the compound is administered orally.

[0053] [A-21] The pharmaceutical composition according to any one of [A-1] to [A-20], wherein the compound is a compound that selectively inhibits the phosphate transporter NaPi-IIb.

[0054] [A-22] The pharmaceutical composition according to any one of [A-1] to [A-21], wherein the compound is a compound that selectively inhibits the phosphate transporter NaPi-IIb, and the compound has a 50% phosphate uptake inhibition concentration (IC) in cells expressing NaPi-IIb or Pitl. 50 ) ratio (IC 50 [Pit1] / IC 50 [NaPi-IIb]), which is 10 or greater.

[0055] [A-23] The pharmaceutical composition according to any one of [A-1] to [A-22], wherein the compound is a compound that selectively inhibits the phosphate transporter NaPi-IIb, and the compound has a 50% phosphate uptake inhibition concentration (IC) in cells expressing NaPi-IIb or Pit2. 50 ) ratio (IC 50 [Pit2] / IC 50 [NaPi-IIb]), which is 10 or greater.

[0056] [A-24] The pharmaceutical composition according to any one of [A-1] to [A-23], wherein the compound has a 50% phosphate uptake inhibition concentration (IC 50 ), which is 10 μg / mol or less.

[0057] [A-25] The pharmaceutical composition according to any one of [A-1] to [A-24], wherein the compound has a 50% phosphate uptake inhibition concentration (IC 50 ), which is 5 μg / mol or less.

[0058] [A-26] The pharmaceutical composition according to any one of [A-1] to [A-25], wherein the compound has a 50% phosphate uptake inhibition concentration (IC 50 ), which is 1 μg / mol or less.

[0059] [A-27] The pharmaceutical composition according to any one of [A-1] to [A-26], wherein the compound is selected from the group consisting of compounds represented by Formula 1 to Formula 11:

[0060] [Chemical formula 1]

[0061]

[0062] [Chemical formula 2]

[0063]

[0064] [Chemical formula 3]

[0065]

[0066] [Chemical formula 4]

[0067]

[0068] or a salt thereof, or a solvate thereof.

[0069] [A-28] The pharmaceutical composition according to any one of [A-1] to [A-26], wherein the compound is a compound selected from the group consisting of compounds represented by Formula 1 to Formula 4 above, or a salt thereof, or a solvate thereof.

[0070] [A-29] The pharmaceutical composition according to any one of [A-1] to [A-28], wherein the cystic disease is a disease in a mammal.

[0071] [A-30] The pharmaceutical composition according to [A-29], wherein the mammal is a human.

[0072] [A-31] The pharmaceutical composition according to any one of [A-1] to [A-30], wherein the cystic disease is selected from the group consisting of cystic kidney disease, polycystic liver disease, cystic lung disease and pancreatic cyst.

[0073] [A-32] The pharmaceutical composition according to any one of [A-2] to [A-30], wherein the cystic disease involves the formation or dilation of utricles in the kidney, liver, lung, or pancreas.

[0074] [A-33] The pharmaceutical composition according to any one of [A-1] to [A-32], which is used for inhibiting a phosphate transporter expressed in the kidney, liver, lung or pancreas.

[0075] [A-34] The pharmaceutical composition according to any one of [A-1] to [A-33], which is used for treating or preventing cystic kidney disease.

[0076] [A-35] The pharmaceutical composition according to any one of [A-1] to [A-34], which is used for treating or preventing polycystic kidney disease.

[0077] [A-36] The pharmaceutical composition according to [A-35], wherein the polycystic kidney disease is autosomal dominant polycystic kidney disease.

[0078] [A-37] The pharmaceutical composition according to any one of [A-1] to [A-36], which is used for inhibiting the formation or expansion of a renal cyst.

[0079] [B-1] A method for treating or preventing a cystic disease, comprising administering to a subject in need thereof an effective amount of a compound that inhibits a phosphate transporter.

[0080] [B-2] A method for inhibiting the formation or expansion of a cyst, comprising administering to a subject in need thereof an effective amount of a compound that inhibits a phosphate transporter.

[0081] [B-3] The method according to [B-1] or [B-2], wherein the phosphate transporter is at least one selected from the group consisting of NaPi-IIa, NaPi-IIb, and NaPi-IIc.

[0082] [B-4] The method according to any one of [B-1] to [B-3], wherein the phosphate transporter is NaPi-IIb.

[0083] [B-5] The method according to any one of [B-1], [B-3] and [B-4], wherein the cystic disease is a disease in which NaPi-IIb is highly expressed in an organ that develops cystic disease.

[0084] [B-6] The method according to any one of [B-1] and [B-3] to [B-5], wherein the cystic disease is a disease involving NaPi-IIb.

[0085] [B-7] The method according to any one of [B-2] to [B-4], wherein NaPi-IIb is highly expressed in cells of the cyst.

[0086] [B-8] The method according to any one of [B-2] to [B-4] and [B-7], wherein the cyst is a cyst involving NaPi-IIb.

[0087] [B-9] The method according to any one of [B-1] to [B-8], wherein the compound is at least one selected from the group consisting of low molecular weight compounds, polypeptides, and polynucleotides.

[0088] [B-10] The method according to any one of [B-1] to [B-9], wherein the compound is a low molecular compound having a molecular weight of 2000 g / mol or less.

[0089] [B-11] The method according to any one of [B-1] to [B-9], wherein the compound is a low molecular compound having a molecular weight of 1000 g / mol or less.

[0090] [B-12] The method according to any one of [B-1] to [B-9], wherein the compound is a polypeptide comprising an antibody.

[0091] [B-13] The method according to any one of [B-1] to [B-9], wherein the compound is an anti-phosphate transporter antibody.

[0092] [B-14] The method according to any one of [B-1] to [B-13], wherein the compound is at least one selected from the group consisting of anti-NaPi-IIa antibodies, anti-NaPi-IIb antibodies, and anti-NaPi-IIc antibodies.

[0093] [B-15] The method according to any one of [B-1] to [B-9], wherein the compound is an anti-NaPi-IIb antibody.

[0094] [B-16] The method according to any one of [B-1] to [B-9], wherein the compound is a polynucleotide selected from the group consisting of ribozymes, antisense molecules, inhibitor oligonucleotides, aptamers, microRNAs, and small interfering RNAs (siRNAs).

[0095] [B-17] The method according to any one of [B-1] to [B-9], wherein the compound is a polynucleotide selected from the group consisting of an antisense molecule, a microRNA, and a small interfering RNA (siRNA).

[0096] [B-18] The method according to any one of [B-1] to [B-17], wherein the compound is at least one selected from the following (i) to (iii):

[0097] (i) low molecular weight compounds having a molecular weight of 2000 g / mol or less;

[0098] (ii) anti-NaPi-IIb antibodies; and

[0099] (iii) a polynucleotide selected from the group consisting of an antisense molecule, a microRNA, and a small interfering RNA (siRNA).

[0100] [B-19] The method according to any one of [B-1] to [B-18], wherein the compound is administered parenterally.

[0101] [B-20] The method according to any one of [B-1] to [B-11] and [B-18], wherein the compound is administered orally.

[0102] [B-21] The method according to any one of [B-1] to [B-20], wherein the compound is a compound that selectively inhibits the phosphate transporter NaPi-IIb.

[0103] [B-22] The method according to any one of [B-1] to [B-21], wherein the compound is a compound that selectively inhibits the phosphate transporter NaPi-IIb, and the compound has a 50% phosphate uptake inhibition concentration (IC) in cells expressing NaPi-IIb or Pit1. 50 ) ratio (IC 50 [Pit1] / IC 50 [NaPi-IIb]), which is 10 or greater.

[0104] [B-23] The method according to any one of [B-1] to [B-22], wherein the compound is a compound that selectively inhibits NaPi-IIb of the phosphate transporter, and the compound has an IC 50 Ratio (IC 50 [Pit2] / IC 50 [NaPi-IIb]), which is 10 or greater.

[0105] [B-24] The method according to any one of [B-1] to [B-23], wherein the compound has a 50% phosphate uptake inhibition concentration (IC 50 ), which is 10 μg / mol or less.

[0106] [B-25] The method according to any one of [B-1] to [B-24], wherein the compound has an IC of inhibitory activity against human NaPi-IIb. 50 , which is 5 μg / mol or less.

[0107] [B-26] The method according to any one of [B-1] to [B-25], wherein the compound has an IC of inhibitory activity against human NaPi-IIb. 50 , which is 1 μg / mol or less.

[0108] [B-27] The method according to any one of [B-1] to [B-20], wherein the compound is a compound selected from the group consisting of compounds represented by Formula 1 to Formula 11 above, or a salt thereof, or a solvate thereof.

[0109] [B-28] The method according to any one of [B-1] to [B-20], wherein the compound is a compound selected from the group consisting of compounds represented by Formula 1 to Formula 4 above, or a salt thereof, or a solvate thereof.

[0110] [B-29] The method according to any one of [B-1] to [B-28], wherein the subject is a mammal.

[0111] [B-30] The method according to [B-29], wherein the mammal is a human.

[0112] [B-31] The method according to any one of [B-1] to [B-30], wherein the cystic disease is selected from the group consisting of cystic kidney disease, polycystic liver disease, cystic lung disease, and pancreatic cysts.

[0113] [B-32] The method according to any one of [B-2] to [B-30], wherein the cystic disease involves the formation or dilation of a utricle in the kidney, liver, lung, or pancreas.

[0114] [B-33] The method according to any one of [B-1] to [B-32], wherein the compound inhibits a phosphate transporter expressed in the kidney, liver, lung, or pancreas.

[0115] [B-34] The method according to any one of [B-1] to [B-33], which is used for treating or preventing cystic kidney disease.

[0116] [B-35] The method according to any one of [B-1] to [B-34], which is used for treating or preventing polycystic kidney disease.

[0117] [B-36] The method according to [B-35], wherein the polycystic kidney disease is autosomal dominant polycystic kidney disease.

[0118] [B-37] The method according to any one of [B-1] to [B-36], which is used to inhibit the formation or expansion of a renal cyst.

[0119] [C-1] Use of a compound that inhibits phosphate transporters in the manufacture of a medicament for treating or preventing cystic diseases.

[0120] [C-2] Use of a compound that inhibits phosphate transporters in the manufacture of a medicament for inhibiting the formation or expansion of a cyst.

[0121] [C-3] The use according to [C-1] or [C-2], wherein the phosphate transporter is at least one selected from the group consisting of NaPi-IIa, NaPi-IIb and NaPi-IIc.

[0122] [C-4] The use according to any one of [C-1] to [C-3], wherein the phosphate transporter is NaPi-IIb.

[0123] [C-5] The use according to any one of [C-1], [C-3] and [C-4], wherein the cystic disease is a disease in which NaPi-IIb is highly expressed in an organ that develops cystic disease.

[0124] [C-6] The use according to any one of [C-1] and [C-3] to [C-5], wherein the cystic disease is a disease involving NaPi-IIb.

[0125] [C-7] The use according to any one of [C-2] to [C-4], wherein NaPi-IIb is highly expressed in cells of the cyst.

[0126] [C-8] The use according to any one of [C-2] to [C-4] and [C-7], wherein the cyst is a cyst involving NaPi-IIb.

[0127] [C-9] The use according to any one of [C-1] to [C-8], wherein the compound is at least one selected from the group consisting of low molecular weight compounds, polypeptides, and polynucleotides.

[0128] [C-10] The use according to any one of [C-1] to [C-9], wherein the compound is a low molecular weight compound having a molecular weight of 2000 g / mol or less.

[0129] [C-11] The use according to any one of [C-1] to [C-9], wherein the compound is a low molecular weight compound having a molecular weight of 1000 g / mol or less.

[0130] [C-12] The use according to any one of [C-1] to [C-9], wherein the compound is a polypeptide comprising an antibody.

[0131] [C-13] The use according to any one of [C-1] to [C-9], wherein the compound is an anti-phosphate transporter antibody.

[0132] [C-14] The use according to any one of [C-1] to [C-13], wherein the compound is at least one selected from the group consisting of anti-NaPi-IIa antibodies, anti-NaPi-IIb antibodies, and anti-NaPi-IIc antibodies.

[0133] [C-15] The use according to any one of [C-1] to [C-9], wherein the compound is an anti-NaPi-IIb antibody.

[0134] [C-16] The use according to any one of [C-1] to [C-9], wherein the compound is a polynucleotide selected from the group consisting of a ribozyme, an antisense molecule, an inhibitor oligonucleotide, an aptamer, a microRNA, and a small interfering RNA (siRNA).

[0135] [C-17] The use according to any one of [C-1] to [C-9], wherein the compound is a polynucleotide selected from the group consisting of an antisense molecule, a microRNA, and a small interfering RNA (siRNA).

[0136] [C-18] The use according to any one of [C-1] to [C-17], wherein the compound is at least one selected from the following (i) to (iii):

[0137] (i) low molecular weight compounds having a molecular weight of 2000 g / mol or less;

[0138] (ii) anti-NaPi-IIb antibodies; and

[0139] (iii) a polynucleotide selected from the group consisting of an antisense molecule, a microRNA, and a small interfering RNA (siRNA).

[0140] [C-19] The use according to any one of [C-1] to [C-18], wherein the compound is administered parenterally.

[0141] [C-20] The use according to any one of [C-1] to [C-11] and [C-18], wherein the compound is administered orally.

[0142] [C-21] The use according to any one of [C-1] to [C-20], wherein the compound is a compound that selectively inhibits the phosphate transporter NaPi-IIb.

[0143] [C-22] The use according to any one of [C-1] to [C-21], wherein the compound is a compound that selectively inhibits the phosphate transporter NaPi-IIb, and the compound has a 50% phosphate uptake inhibition concentration (IC) in cells expressing NaPi-IIb or Pitl. 50 ) ratio (IC 50 [Pit1] / IC 50 [NaPi-IIb]), which is 10 or greater.

[0144] [C-23] The use according to any one of [C-1] to [C-22], wherein the compound is a compound that selectively inhibits NaPi-IIb of the phosphate transporter, and the compound has an IC 50 Ratio (IC 50 [Pit2] / IC 50 [NaPi-IIb]), which is 10 or greater.

[0145] [C-24] The use according to any one of [C-1] to [C-23], wherein the compound has a 50% phosphate uptake inhibition concentration (IC 50 ), which is 10 μg / mol or less.

[0146] [C-25] The use according to any one of [C-1] to [C-24], wherein the compound has an IC of 1.000 for inhibitory activity against human NaPi-IIb. 50 , which is 5 μg / mol or less.

[0147] [C-26] The use according to any one of [C-1] to [C-25], wherein the compound has an IC of inhibitory activity against human NaPi-IIb. 50 , which is 1 μg / mol or less.

[0148] [C-27] The use according to any one of [C-1] to [C-20], wherein the compound is a compound selected from the group consisting of compounds represented by Formula 1 to Formula 11 above, or a salt thereof, or a solvate thereof.

[0149] [C-28] The use according to any one of [C-1] to [C-20], wherein the compound is a compound selected from the group consisting of compounds represented by Formula 1 to Formula 4 above, or a salt thereof, or a solvate thereof.

[0150] [C-29] The use according to any one of [C-1] to [C-28], wherein the cystic disease is a disease in a mammal.

[0151] [C-30] The use according to [C-29], wherein the mammal is a human.

[0152] [C-31] The use according to any one of [C-1] to [C-30], wherein the cystic disease is selected from the group consisting of cystic kidney disease, polycystic liver disease, cystic lung disease and pancreatic cysts.

[0153] [C-32] The use according to any one of [C-2] to [C-30], wherein the cystic disease involves the formation or dilation of utricles in the kidney, liver, lung or pancreas.

[0154] [C-33] The use according to any one of [C-1] to [C-32], which is used to inhibit a phosphate transporter expressed in the kidney, liver, lung or pancreas.

[0155] [C-34] The use according to any one of [C-1] to [C-33], which is used for treating or preventing cystic kidney disease.

[0156] [C-35] The use according to any one of [C-1] to [C-34], which is used for treating or preventing polycystic kidney disease.

[0157] [C-36] The use according to [C-35], wherein the polycystic kidney disease is autosomal dominant polycystic kidney disease.

[0158] [C-37] The use according to any one of [C-1] to [C-36], which is used for inhibiting the formation or expansion of renal cysts.

[0159] [D-1] A compound that inhibits phosphate transporter, which is useful for treating or preventing cystic diseases.

[0160] [D-2] A compound that inhibits phosphate transporter, for use in inhibiting the formation or expansion of renal cysts.

[0161] [D-3] The compound according to [D-1] or [D-2], wherein the phosphate transporter is at least one selected from the group consisting of NaPi-IIa, NaPi-IIb, and NaPi-IIc.

[0162] [D-4] The compound according to any one of [D-1] to [D-3], wherein the phosphate transporter is NaPi-IIb.

[0163] [D-5] The compound according to any one of [D-1], [D-3] and [D-4], wherein the cystic disease is a disease in which NaPi-IIb is highly expressed in an organ that develops cystic disease.

[0164] [D-6] The compound according to any one of [D-1] and [D-3] to [D-5], wherein the cystic disease is a disease involving NaPi-IIb.

[0165] [D-7] The compound according to any one of [D-2] to [D-4], wherein NaPi-IIb is highly expressed in cells of cysts.

[0166] [D-8] The compound according to any one of [D-2] to [D-4] and [D-7], wherein the cyst is a cyst involving NaPi-IIb.

[0167] [D-9] The compound according to any one of [D-1] to [D-8], wherein the compound is at least one selected from the group consisting of low molecular weight compounds, polypeptides, and polynucleotides.

[0168] [D-10] The compound according to any one of [D-1] to [D-9], wherein the compound is a low molecular compound having a molecular weight of 2000 g / mol or less.

[0169] [D-11] The compound according to any one of [D-1] to [D-9], wherein the compound is a low molecular compound having a molecular weight of 1000 g / mol or less.

[0170] [D-12] The compound according to any one of [D-1] to [D-9], wherein the compound is a polypeptide comprising an antibody.

[0171] [D-13] The compound according to any one of [D-1] to [D-9], wherein the compound is an anti-phosphate transporter antibody.

[0172] [D-14] The compound according to any one of [D-1] to [D-13], wherein the compound is at least one selected from the group consisting of anti-NaPi-IIa antibodies, anti-NaPi-IIb antibodies, and anti-NaPi-IIc antibodies.

[0173] [D-15] The compound according to any one of [D-1] to [D-9], wherein the compound is an anti-NaPi-IIb antibody.

[0174] [D-16] The compound according to any one of [D-1] to [D-9], wherein the compound is a polynucleotide selected from the group consisting of ribozymes, antisense molecules, inhibitor oligonucleotides, aptamers, microRNAs, and small interfering RNAs (siRNAs).

[0175] [D-17] The compound according to any one of [D-1] to [D-9], wherein the compound is a polynucleotide selected from the group consisting of an antisense molecule, a microRNA, and a small interfering RNA (siRNA).

[0176] [D-18] The compound according to any one of [D-1] to [D-17], wherein the compound is at least one selected from the following (i) to (iii):

[0177] (i) low molecular weight compounds having a molecular weight of 2000 g / mol or less;

[0178] (ii) anti-NaPi-IIb antibodies; and

[0179] (iii) a polynucleotide selected from the group consisting of an antisense molecule, a microRNA, and a small interfering RNA (siRNA).

[0180] [D-19] The compound according to any one of [D-1] to [D-18], wherein the compound is administered parenterally.

[0181] [D-20] The compound according to any one of [D-1] to [D-11] and [D-18], wherein the compound is administered orally.

[0182] [D-21] The compound according to any one of [D-1] to [D-20], wherein the compound is a compound that selectively inhibits NaPi-IIb, a phosphate transporter.

[0183] [D-22] The compound according to any one of [D-1] to [D-21], wherein the compound is a compound that selectively inhibits the phosphate transporter NaPi-IIb, and the compound has a 50% phosphate uptake inhibition concentration (IC 50 ) ratio (IC 50 [Pit1] / IC 50 [NaPi-IIb]), which is 10 or greater.

[0184] [D-23] The compound according to any one of [D-1] to [D-22], wherein the compound is a compound that selectively inhibits NaPi-IIb of the phosphate transporter, and the compound has an IC 50 Ratio (IC 50 [Pit2] / IC 50 [NaPi-IIb]), which is 10 or greater.

[0185] [D-24] The compound according to any one of [D-1] to [D-23], wherein the compound has a 50% phosphate uptake inhibition concentration (IC 50 ), which is 10 μg / mol or less.

[0186] [D-25] The compound according to any one of [D-1] to [D-24], wherein the compound has an IC of inhibitory activity against human NaPi-IIb. 50 , which is 5 μg / mol or less.

[0187] [D-26] The compound according to any one of [D-1] to [D-25], wherein the compound has an IC of inhibitory activity against human NaPi-IIb. 50 , which is 1 μg / mol or less.

[0188] [D-27] The compound according to any one of [D-1] to [D-20], wherein the compound is a compound selected from the group consisting of compounds represented by Formula 1 to Formula 11 above, or a salt thereof, or a solvate thereof.

[0189] [D-28] The compound according to any one of [D-1] to [D-20], wherein the compound is a compound selected from the group consisting of compounds represented by Formula 1 to Formula 4 above, or a salt thereof, or a solvate thereof.

[0190] [D-29] The compound according to any one of [D-1] to [D-28], wherein the cystic disease is a disease in a mammal.

[0191] [D-30] The compound according to [D-29], wherein the mammal is a human.

[0192] [D-31] The compound according to any one of [D-1] to [D-30], wherein the cystic disease is selected from the group consisting of cystic kidney disease, polycystic liver disease, cystic lung disease and pancreatic cyst.

[0193] [D-32] The compound according to any one of [D-2] to [D-30], wherein the cystic disease involves the formation or dilation of utricles in the kidney, liver, lung or pancreas.

[0194] [D-33] The compound according to any one of [D-1] to [D-32], which is used for inhibiting a phosphate transporter expressed in the kidney, liver, lung or pancreas.

[0195] [D-34] The compound according to any one of [D-1] to [D-33], which is used for treating or preventing cystic kidney disease.

[0196] [D-35] The compound according to any one of [D-1] to [D-34], which is used for treating or preventing polycystic kidney disease.

[0197] [D-36] The compound according to [D-35], wherein the polycystic kidney disease is autosomal dominant polycystic kidney disease.

[0198] [D-37] The compound according to any one of [D-1] to [D-36], which is used for inhibiting the formation or expansion of renal cysts.

[0199] [E-1] A method for predicting the effect of treatment with a pharmaceutical agent in a patient suffering from a cystic disease, the method comprising:

[0200] Confirmation of NaPi-IIb expression in cells collected from organs of patients who had developed cysts: and

[0201] The patient in whom the expression is confirmed is determined to be a patient who will obtain the therapeutic effect,

[0202] The drug is an inhibitor of NaPi-IIb.

[0203] [E-2] The method according to [E-1], wherein the cystic disease is cystic kidney disease.

[0204] [E-3] The method according to [E-1] or [E-2], wherein the cystic disease is polycystic kidney disease.

[0205] [E-4] The method according to [E-3], wherein the polycystic kidney disease is autosomal dominant polycystic kidney disease.

[0206] [E-5] The method according to any one of [E-1] to [E-4], wherein the inhibitor is a low molecular weight compound, a polynucleotide, or a polypeptide.

[0207] [E-6] The pharmaceutical composition according to any one of [E-1] to [E-5], wherein the inhibitor is a low molecular weight compound having a molecular weight of 2000 g / mol or less.

[0208] [E-7] The pharmaceutical composition according to any one of [E-1] to [E-6], wherein the inhibitor is a low molecular weight compound having a molecular weight of 1000 g / mol or less.

[0209] [E-8] The method according to any one of [E-1] to [E-5], wherein the inhibitor comprises an antibody or a binding fragment thereof.

[0210] [E-9] The method according to any one of [E-1] to [E-5], wherein the inhibitor is an anti-phosphate transporter antibody.

[0211] [E-10] The method according to any one of [E-1] to [E-5], wherein the inhibitor is at least one selected from the group consisting of anti-NaPi-IIa antibodies, anti-NaPi-IIb antibodies, and anti-NaPi-IIc antibodies.

[0212] [E-11] The method according to any one of [E-1] to [E-5], wherein the inhibitor is an anti-NaPi-IIb antibody.

[0213] [E-12] The method according to any one of [E-1] to [E-5], wherein the inhibitor is a polynucleotide selected from the group consisting of a ribozyme, an antisense molecule, an inhibitor oligonucleotide, an aptamer, a microRNA, and a small interfering RNA (siRNA).

[0214] [E-13] The pharmaceutical composition according to any one of [E-1] to [E-5], wherein the inhibitor is a polynucleotide selected from the group consisting of an antisense molecule, a microRNA, and a small interfering RNA (siRNA).

[0215] [E-14] The pharmaceutical composition according to any one of [E-1] to [E-5], wherein the inhibitor is at least one selected from the following (i) to (iii):

[0216] (i) low molecular weight compounds having a molecular weight of 2000 g / mol or less;

[0217] (ii) anti-NaPi-IIb antibodies; and

[0218] (iii) a polynucleotide selected from the group consisting of an antisense molecule, a microRNA, and a small interfering RNA (siRNA).

[0219] [E-15] The method according to any one of [E-1] to [E-14], wherein the inhibitor is administered parenterally.

[0220] [E-16] The method according to any one of [E-1] to [E-7] and [E-14], wherein the inhibitor is administered orally.

[0221] [E-17] The method according to any one of [E-1] to [E-16], wherein the inhibitor is a compound that selectively inhibits the phosphate transporter NaPi-IIb.

[0222] [E-18] The method according to any one of [E-1] to [E-17], wherein the compound is a compound that selectively inhibits the phosphate transporter NaPi-IIb, and the compound has a 50% phosphate uptake inhibition concentration (IC) in cells expressing NaPi-IIb or Pit1. 50 ) ratio (IC 50 [Pit1] / IC 50 [NaPi-IIb]), which is 10 or greater.

[0223] [E-19] The method according to any one of [E-1] to [E-18], wherein the compound is a compound that selectively inhibits the phosphate transporter NaPi-IIb, and the compound has a 50% phosphate uptake inhibition concentration (IC) in cells expressing NaPi-IIb or Pit2. 50 ) ratio (IC 50 [Pit2] / IC 50 [NaPi-IIb]), which is 10 or greater.

[0224] [E-20] The method according to any one of [E-1] to [E-19], wherein the compound has a 50% phosphate uptake inhibition concentration (IC 50 ), which is 10 μg / mol or less.

[0225] [E-21] The method according to any one of [E-1] to [E-20], wherein the compound has a 50% phosphate uptake inhibition concentration (IC 50 ), which was 5 μg / mol or less.

[0226] [E-22] The method according to any one of [E-1] to [E-21], wherein the compound has a 50% phosphate uptake inhibition concentration (IC 50 ), which is 1 μg / mol or less.

[0227] [E-23] The method according to any one of [E-1] to [E-19], wherein the inhibitor is a compound selected from the group consisting of compounds of Formula 1 to Formula 11 above.

[0228] [E-24] The method according to any one of [E-1] to [E-19], wherein the inhibitor is a compound selected from the group consisting of compounds of Formula 1 to Formula 4 above.

[0229] [E-25] The method according to any one of [E-1] to [E-24], wherein the cystic disease is a disease in a mammal.

[0230] [E-26] The method according to [E-25], wherein the mammal is a human.

[0231] [E-27] The method according to any one of [E-1] to [E-26], wherein the cystic disease is cystic kidney disease, polycystic liver disease, cystic lung disease, or pancreatic cyst.

[0232] [E-28] The method according to any one of [E-2] to [E-26], wherein the cyst is a cyst developed in the kidney, liver, lung or pancreas.

[0233] [E-29] The method according to any one of [E-1] to [E-28], wherein the cell is a kidney cell contained in a biological sample from a patient.

[0234] [F-1] A pharmaceutical composition comprising a compound that inhibits phosphate transporters as an active ingredient, for use in inhibiting renal cystogenesis in a subject at risk of autosomal dominant polycystic kidney disease.

[0235] [F-2] The pharmaceutical composition according to [F-1], wherein the subject has a confirmed familial occurrence of autosomal dominant polycystic kidney disease.

[0236] [F-3] The pharmaceutical composition according to [F-1] or [F-2], wherein one of the subject's parents is a patient suffering from chromosomal dominant hereditary polycystic kidney disease.

[0237] [F-4] The pharmaceutical composition according to any one of [F-1] to [F-3], wherein the subject has a PKD1 or PKD2 deficiency.

[0238] [F-5] The pharmaceutical composition according to any one of [F-1] to [F-4], wherein the subject has PKD1 deficiency.

[0239] [F-6] The pharmaceutical composition according to any one of [F-1] to [F-5], wherein the subject is 30 years old or older.

[0240] [F-7] The pharmaceutical composition according to any one of [F-1] to [F-6], wherein the subject is confirmed to have three or more cysts in each kidney on both sides by CT, MRI or ultrasonic tomography.

[0241] [F-8] The pharmaceutical composition according to any one of [F-1] to [F-7], wherein the subject has been diagnosed with autosomal dominant polycystic kidney disease.

[0242] [F-9] The pharmaceutical composition according to any one of [F-1] to [F-8], wherein the phosphate transporter is at least one selected from the group consisting of NaPi-IIa, NaPi-IIb and NaPi-IIc.

[0243] [F-10] The pharmaceutical composition according to any one of [F-1] to [F-9], wherein the phosphate transporter is NaPi-IIb.

[0244] [F-11] The pharmaceutical composition according to any one of [F-1] to [F-10], wherein NaPi-IIb is expressed in kidney cells of the subject.

[0245] [F-12] The pharmaceutical composition according to any one of [F-1] to [F-11], wherein the compound is a compound that inhibits a phosphate transporter expressed in the kidney.

[0246] [F-13] The pharmaceutical composition according to any one of [F-1] to [F-12], wherein the compound is a low molecular weight compound, a polynucleotide and a polypeptide.

[0247] [F-14] The pharmaceutical composition according to any one of [F-1] to [F-13], wherein the compound is a low molecular weight compound having a molecular weight of 2000 g / mol or less.

[0248] [F-15] The pharmaceutical composition according to any one of [F-1] to [F-13], wherein the compound is a low molecular weight compound having a molecular weight of 1000 g / mol or less.

[0249] [F-16] The pharmaceutical composition according to any one of [F-1] to [F-13], wherein the compound comprises an antibody or a binding fragment thereof.

[0250] [F-17] The pharmaceutical composition according to any one of [F-1] to [F-13], wherein the compound is an anti-phosphate transporter antibody.

[0251] [F-18] The pharmaceutical composition according to any one of [F-1] to [F-13], wherein the compound is at least one selected from the group consisting of anti-NaPi-IIa antibodies, anti-NaPi-IIb antibodies, and anti-NaPi-IIc antibodies.

[0252] [F-19] The pharmaceutical composition according to any one of [F-1] to [F-13], wherein the compound is an anti-NaPi-IIb antibody.

[0253] [F-20] The pharmaceutical composition according to any one of [F-1] to [F-13], wherein the compound is a polynucleotide selected from the group consisting of ribozymes, antisense molecules, inhibitor oligonucleotides, aptamers, microRNAs and small interfering RNAs (siRNAs).

[0254] [F-21] The pharmaceutical composition according to any one of [F-1] to [F-20], wherein the compound is administered parenterally.

[0255] [F-22] The pharmaceutical composition according to any one of [F-1] to [F-15], wherein the compound is administered orally.

[0256] [F-23] The pharmaceutical composition according to any one of [F-1] to [F-18], wherein the compound is a compound that selectively inhibits the phosphate transporter NaPi-IIb.

[0257] [F-24] The pharmaceutical composition according to any one of [F-1] to [F-23], wherein the compound is a compound that selectively inhibits the phosphate transporter NaPi-IIb, and the compound has a 50% phosphate uptake inhibition concentration (IC) in cells expressing NaPi-IIb or Pit2. 50 ) ratio (IC 50 [Pit2] / IC 50 [NaPi-IIb]), which is 10 or greater.

[0258] [F-25] The pharmaceutical composition according to any one of [F-1] to [F-24], wherein the compound has a 50% phosphate uptake inhibition concentration (IC 50 ), which is 10 μg / mol or less.

[0259] [F-26] The pharmaceutical composition according to any one of [F-1] to [F-25], wherein the compound has a 50% phosphate uptake inhibition concentration (IC 50 ), which is 5 μg / mol or less.

[0260] [E-27] The pharmaceutical composition according to any one of [F-1] to [F-26], wherein the compound has a 50% phosphate uptake inhibition concentration (IC 50 ), which is 1 μg / mol or less.

[0261] [F-28] The pharmaceutical composition according to any one of [F-1] to [F-27], wherein the compound is a compound selected from the group consisting of compounds represented by Formula 1 to Formula 11 above, or a salt thereof, or a solvate thereof.

[0262] [F-29] The pharmaceutical composition according to any one of [F-1] to [F-28], wherein the compound is a compound selected from the group consisting of compounds represented by Formula 1 to Formula 4 above, or a salt thereof, or a solvate thereof.

[0263] [G-1] A method for screening a compound for treating or preventing a disease selected from cystic kidney disease, polycystic liver disease, cystic lung disease and pancreatic cyst, the method comprising measuring an inhibitory activity against a phosphate transporter.

[0264] [G-2] A method for screening a compound for inhibiting cyst formation or cyst expansion in an organ of a mammal, the method comprising measuring an inhibitory activity against a phosphate transporter.

[0265] [G-3] The method according to [G-2], wherein the organ is pancreas.

[0266] [G-4] The method according to any one of [G-1] to [G-3], wherein the phosphate transporter is at least one selected from the group consisting of NaPi-IIa, NaPi-IIb, and NaPi-IIc.

[0267] [G-5] The method according to any one of [G-1] to [G-4], wherein the phosphate transporter is NaPi-IIb.

[0268] [G-6] The method according to any one of [G-1] to [G-5], wherein the disease is cystic kidney disease.

[0269] [G-7] The method according to [G-6], wherein the cystic kidney disease is polycystic kidney disease.

[0270] [G-8] The method according to [G-7], wherein the polycystic kidney disease is autosomal dominant polycystic kidney disease.

[0271] [G-9] The method according to any one of [G-1] to [G-8], wherein the disease is a disease in a mammal.

[0272] [G-10] The method according to [G-9], wherein the mammal is a human.

[0273] [G-11] The method according to any one of [G-1] to [G-10], wherein the inhibitory activity is selective inhibitory activity against NaPi-IIb relative to Pit1 or Pit2.

[0274] Advantageous Effects of the Invention

[0275] In one aspect of the present invention, a pharmaceutical composition useful for treating or preventing cystic disease and a medicament for treating or preventing cystic disease are provided. In another aspect of the present invention, a method for predicting the effect of treatment with a pharmaceutical agent in a patient suffering from cystic disease is provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0276] Figure 1a Graphs showing HE staining images and NaPi-IIb expression levels in kidney tissues of ADPKD patients.

[0277] Figure 1b Graphs showing HE staining images and NaPi-IIb expression levels in kidney tissues of ADPKD patients.

[0278] Figure 1c Graphs showing HE staining images and NaPi-IIb expression levels in kidney tissues of ADPKD patients.

[0279] Figure 1d Graphs showing HE staining images and NaPi-IIb expression levels in kidney tissues of ADPKD patients.

[0280] Figure 1e Graphs showing HE staining images and NaPi-IIb expression levels in kidney tissues of ADPKD patients.

[0281] Figure 1f Graphs showing HE staining images and NaPi-IIb expression levels in kidney tissues of ADPKD patients.

[0282] Figure 2a The graphs show HE staining images and NaPi-IIb expression levels in kidney tissues of B6 mice. (a) is the result of B6 mice, (b) is the result of PC1 conditional KO mice, and (c) is the result of Pcy mice.

[0283] Figure 2b Graphs showing HE staining images and NaPi-IIb expression levels in kidney tissues of PC1 conditional knockout mice.

[0284] Figure 2c The graph shows HE staining images and NaPi-IIb expression levels in kidney tissues of Pcy mice.

[0285] Figure 3a Shown are the results of evaluating the effects of tolvaptan and compound 4 on kidney volume in pcy mice.

[0286] Figure 3b Shown are the results of evaluating the effects of tolvaptan and Compound 4 on blood urea nitrogen (UN) concentration in pcy mice.

[0287] Figure 3c Shown are the results of evaluating the effects of tolvaptan and compound 4 on body weight in pcy mice.

[0288] Figure 3d Shown are the results of evaluating the effects of tolvaptan and compound 4 on urine volume in pcy mice.

[0289] Figure 4 The three-dimensional images are of culture wells of kidney tissue of a human ADPKD patient, showing (a) a well without addition of a stimulant and compound 4, (b) a well with addition of a stimulant and without addition of compound 4, and (c) a well with addition of a stimulant and compound 4.

[0290] Figure 5a Shown are the results of evaluating the effects of tolvaptan and compound 4 on kidney volume in PC1 conditional knockout mice.

[0291] Figure 5b Shown are the results of evaluating the effects of tolvaptan and compound 4 on body weight in pcy mice.

[0292] Figure 5c Shown are the results of evaluating the effects of tolvaptan and compound 4 on urine volume in pcy mice. DETAILED DESCRIPTION

[0293] Embodiments of the present invention will be described. However, the present invention is not limited to the following embodiments. The medicine for treating or preventing and the method for treating or preventing according to the present invention can be applied to or applied to people. As used herein, the "to" indicating a numerical range includes values ​​at both ends thereof. For example, "A to B" refers to a numerical range of A or more and B or less. As used herein, when used in combination with a numerical value, the term "about" means a value range of +10% and -10% of the numerical value. As used herein, the term "and / or" is intended to include each combination of the terms "and" and "or" in appropriate combinations. Specifically, for example, the term "A, B and / or C" includes the following seven variations: (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, and (vii) A, B and C.

[0294] The present invention provides a pharmaceutical composition comprising a compound that inhibits phosphate transporters as an active ingredient, which is used for treating or preventing cystic diseases or for inhibiting the formation or expansion of cysts.

[0295] In one aspect of the present invention, "phosphate transporter" is not particularly limited as long as it participates in phosphorus metabolism in the body. Examples include transporters involved in reabsorption from the kidney, absorption from the gastrointestinal tract, and migration to and from bones and other tissues, and transporters involved in maintaining homeostasis of phosphorus metabolism in the body. Phosphate transporters include sodium-dependent phosphate transporters. Sodium-dependent phosphate transporters are sometimes called sodium-phosphate cotransporters and cover type I, II or III phosphate transporters.

[0296] In one aspect of the present invention, examples of the phosphate transporter include NaPi-IIa, NaPi-IIb, NaPi-IIc, Pit1, and Pit2, and preferred examples include NaPi-IIb.

[0297] In one aspect of the present invention, the compound that inhibits phosphate transporters is not particularly limited, as long as it has inhibitory activity against phosphate transporters or inhibits the expression of phosphate transporters. As used herein, the compound that inhibits phosphate transporters may also be referred to as a phosphate transporter inhibitor.

[0298] In one aspect of the present invention, "treatment" means inhibiting the expansion of cysts in an individual's organ, reducing the number of cyst cells, inhibiting the proliferation of cyst cells, reducing the volume of cysts, reducing the weight of cysts, inhibiting the metastasis of cyst cells, or improving various symptoms caused by cysts through the pharmaceutical composition of the present invention. In addition, in some embodiments, "prevention" in the present invention means inhibiting the formation of cysts, preventing the increase in the number of cyst cells due to the re-proliferation of reduced cyst cells, preventing the re-proliferation of cyst cells whose proliferation is inhibited, preventing the re-increase of the reduced cyst size, or preventing the macroscopic reappearance of cysts that have macroscopically disappeared (or healed) due to local treatment.

[0299] As used herein, "pharmaceutical composition" means a mixture comprising specified ingredients in predetermined amounts or ratios.

[0300] In addition to the active ingredient, the pharmaceutical composition may also include a pharmaceutical carrier. As used herein, the term "pharmaceutically acceptable carrier" means one or more solid or liquid excipients, diluents or packaging materials suitable for administration to mammals. As used herein, the term "pharmaceutically acceptable" means that it can be used as a drug in terms of efficacy, safety, etc.

[0301] Examples of additives that can be used as pharmaceutical carriers include: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and derivatives such as sodium carboxymethylcellulose, ethylcellulose and methylcellulose; tragacanth powder; malt: gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter; polyols such as propylene glycol, glycerol, sorbitol, mannitol and polyethylene glycol; alginates; emulsifiers such as TWEEN (R); wetting agents such as lecithin; colorants; flavorings; tableting; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline solution; and phosphate buffered saline.

[0302] In one aspect of the present invention, a method for identifying a target molecule of a drug for treating or preventing a specific disease is provided. For example, a gene suitable as a target of a drug can be identified by a method comprising the following steps to identify a target molecule.

[0303] (1) Identification of genes as disease factors: Genes as disease factors can be identified by analyzing differentially expressed genes (DEGs) in tissues of normal and pathological groups.

[0304] (2) Identifying genes suitable as targets of pharmaceutical agents from the genes identified in (1): Genes suitable as targets of pharmaceutical agents can be identified from genes that are disease factors by combining a plurality of gene selection criteria. Examples of gene selection criteria for selecting genes suitable as targets of pharmaceutical agents include criteria that they are not genes related to innate immunity, acquired immunity, immune cells, and inflammation, criteria that they are not fibrosis-related genes associated with chronic inflammation, and criteria that they are genes related to membrane proteins. All of these gene selection criteria are preferably satisfied.

[0305] In one aspect of the present invention, the expression of NaPi-IIb can be confirmed, for example, according to the method described in NPL 10. More specifically, the expression can be confirmed by the method described below.

[0306] 1) The cyst-containing tissue was excised from the organ and frozen blocks were prepared by OCT embedding.

[0307] 2) The frozen blocks were sectioned and placed on slides for Visium gene expression, and HE staining was performed.

[0308] 3) After obtaining the HE staining image, cDNA was generated and next generation sequence analysis was performed.

[0309] 4) Perform sequence analysis of the short-read sequence library on the cDNA.

[0310] 5) The results of sequence analysis are reflected in the HE staining images.

[0311] 6) The number of each gene in each spot calculated by sequence analysis is corrected by the number of housekeeping genes and the number of nucleic acids in each spot to obtain the value of the expression level of each gene.

[0312] In one aspect of the present invention, high expression of NaPi-IIb refers to, for example, a situation in which, in a HE-stained image of an organ tissue reflecting the sequence analysis results obtained by the above method, NaPi-IIb is expressed in an area of ​​10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more or 90% or more of the entire organ tissue image.

[0313] In one aspect of the invention, a disease involving NaPi-IIb means a cystic disease whose development, progression and / or continuation involves NaPi-IIb. "A cystic disease whose formation, progression and / or continuation involves NaPi-IIb" includes not only a cystic disease whose formation, progression and / or continuation directly involves NaPi-IIb, but also a cystic disease whose formation, progression and / or continuation indirectly involves NaPi-IIb. Cystic diseases involving NaPi-IIb are not particularly limited to, but may mean, for example, a cystic disease whose formation, progression and / or continuation involves an increase in NaPi-IIb.

[0314] In one aspect of the invention, a cyst involving NaPi-IIb means a cyst whose formation, expansion, progression and / or continuation involves NaPi-IIb. "A cyst whose formation, expansion, progression and / or continuation involves NaPi-IIb" includes not only a cyst whose formation, expansion, progression and / or continuation directly involves NaPi-IIb, but also a cyst whose formation, expansion, progression and / or continuation indirectly involves NaPi-IIb. A cyst involving NaPi-IIb is not particularly limited to, but may mean, for example, a cyst whose formation, expansion, progression and / or continuation involves an increase in NaPi-IIb.

[0315] In one aspect of the present invention, the compound that inhibits phosphate transporter is not particularly limited and may be a known compound and may be a compound identified by screening as described below, but is preferably at least one selected from the group consisting of a low molecular weight compound, a polypeptide and a polynucleotide.

[0316] Polypeptide includes not only the full-length polypeptide encoded by gene, but also its fragment, chemically synthesized polypeptide, cyclic polypeptide and glycopeptide.Polypeptide also includes antibody and antigen peptide, and antibody can be polyclonal antibody or monoclonal antibody.In addition to complete antibody, antibody also includes antibody fragment (such as Fab, Fab', F(ab')2, Fv, scFv, sc(Fv)2, dsFv, diabody, etc.), its polymer, low-molecular antibody in which the variable region of antibody is combined, and antibody-drug conjugate (ADC).Antibody is preferably anti-phosphate transporter antibody, more preferably at least one selected from the group consisting of anti-NaPi-IIa antibody, anti-NaPi-IIb antibody and anti-NaPi-IIc antibody, and further preferably anti-NaPi-IIb antibody.

[0317] The example of polynucleotide includes ribozyme, antisense molecule, inhibitor oligonucleotide, aptamer, microRNA and small interfering RNA (siRNA), and preferred example includes antisense molecule, microRNA and siRNA. Polynucleotide includes not only full-length polynucleotide, but also its fragment and synthetic polynucleotide. The unit of molecular weight in the present disclosure is "g / mol" (hereinafter, the unit of molecular weight can be omitted in this specification). According to one aspect of the present invention, compound is a compound with a molecular weight of 2000g / mol or less, 1800g / mol or less, 1600g / mol or less, 1400g / mol or less, 1200g / mol or less, 1000g / mol or less, 800g / mol or less, 600g / mol or less, 400g / mol or less or 200g / mol or less. Specific examples thereof include compounds described in WO2012 / 006475, WO2011 / 136269, WO2013 / 062065, WO2013 / 082756, WO2013 / 082751 and WO2013 / 129435, salts thereof, or solvates thereof. More specific examples include the following compounds represented by Formula 1 to Formula 11, or pharmaceutically acceptable salts thereof.

[0318] [Chemical formula 5]

[0319]

[0320] [Chemical formula 6]

[0321]

[0322] [Chemical formula 7]

[0323]

[0324] [Chemical formula 8]

[0325]

[0326] [Chemical formula 9]

[0327]

[0328] [Chemical formula 10]

[0329]

[0330] When using the pharmaceutical composition of the present invention, its method of application can be oral method or parenteral method.The example of parenteral method of application includes rectal, intravenous, intramuscular, subcutaneous, intracisternal, intravaginal, intraperitoneal, intravesical or local (infusion, powder, ointment, gel or emulsifiable paste) application and suction (oral spray or nasal spray).The example of its dosage form includes tablet, capsule, granule, powder, pill, aqueous and non-aqueous oral solution and suspension, and the parenteral solution in the container that is suitable for being subdivided into single dose.This dosage form can also be suitable for multiple methods of application, and this multiple methods of application covers modified release preparation, such as subcutaneous transplantation.

[0331] The above-mentioned preparation is produced by a well-known method using additives such as an excipient, a lubricant (coating agent), a binder, a disintegrant, a stabilizer, a flavoring agent, and a diluent.

[0332] Examples of the excipient include starches (such as starch, potato starch, and corn starch), lactose, crystalline cellulose, calcium hydrogen phosphate.

[0333] Examples of the coating agent include ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, shellac, talc, carnauba wax, and paraffin.

[0334] Examples of binders include polyvinyl pyrrolidone, polyethylene glycol, and similar compounds as excipients.

[0335] Examples of disintegrants include similar compounds to the excipients and chemically modified starches and celluloses, such as cross-linked sodium carboxymethylcellulose, sodium carboxymethyl starch, and cross-linked polyvinyl pyrrolidone.

[0336] Examples of the stabilizer include parabens such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol, phenethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.

[0337] Examples of flavoring agents include commonly used sweeteners, acidulants, and spices.

[0338] Examples of solvents used in the production of liquid medicines include ethanol, phenol, chlorocresol, purified water, and distilled water.

[0339] Examples of surfactants or emulsifiers include polyethylene glycol 40 stearate and lauromacrogol.

[0340] In one aspect of the present invention, when using a pharmaceutical composition, the amount used varies depending on symptoms, age, body weight, relative health status, the presence of other drugs, administration methods, etc. For example, for patients (warm-blooded animals, especially humans), in the case of oral medicaments, the general effective amount is preferably 1 mg / kg body weight / day to 20 mg / kg body weight / day, more preferably 1 mg / kg body weight to 10 mg / kg body weight, which is an active ingredient (using the compound described herein as an active ingredient), and for adult patients with normal body weight, the amount used per day is preferably in the range of 60 mg to 1200 mg. However, the amount is not necessarily limited to these values.

[0341] In one aspect of the present invention, the inhibitory activity of the compound that inhibits the phosphate transporter can be confirmed by a known measurement method. Here, the index for confirming the inhibitory activity can be, for example, the 50% phosphate uptake inhibition concentration (IC) in cells expressing the phosphate transporter as measured by the method described in NPL 8. 50 ). That is, it can be measured by the following method.

[0342] 1) Transfect human NaPi-IIb expression plasmid, human PiT1 expression plasmid or human PiT2 expression plasmid into CHO cells.

[0343] 2) The culture medium was replaced with buffer A (145 mM choline chloride, 3 mM KCl, 1 mM CaCl2, 0.5 mM MgCl2, 5 mM glucose, 5 mM MES (pH 6.5)), and then replaced with buffer B (145 mM NaCl, 3 mM KCl, 1 mM CaCl2, 0.5 mM MgCl2, 5 mM glucose, 5 mM MES (pH 6.5)), to which the test compound was added at a final concentration of 0.01, 0.03, 0.1, 0.3, 1, 3, 10 or 30 μM, to which buffer A was added with DMSO, or to which buffer B was added with DMSO.

[0344] 3) After a certain period of time, add 1 / 20 of the amount of 33 PO4 buffer A and react at room temperature.

[0345] 4) After washing with ice-cold buffer A, add liquid scintillant and measure 33 PO4 uptake. The inhibition rate can be determined by the following formula.

[0346] Inhibition rate (%) = (1-(the number of wells treated with buffer B to which the test compound was added) 33PO4 uptake - wells treated with buffer A with DMSO added 33 PO4 uptake) / (DMSO-added wells treated with buffer B 33 PO4 uptake - wells treated with buffer A with DMSO added 33 PO4)) x 100

[0347] 5) 50% in cells expressing human NaPi-IIb, human PiT1, and human PiT2 33 PO4 uptake inhibition concentration (IC 50 )(μM) was calculated from a straight line passing through two points sandwiching 50% inhibition.

[0348] In one aspect of the invention, the 50% phosphate uptake inhibition concentration (IC 50 ) is 10 μM or less, 5 μM or less or 1 μM or less. In one aspect of the present invention, the 50% phosphate uptake inhibition concentration (IC 50 ) is 10 μM or less, 5 μM or less or 1 μM or less.

[0349] In one aspect of the present invention, the compound that inhibits phosphate transporters is a compound that selectively inhibits NaPi-IIb, and for example, can be a compound that selectively inhibits NaPi-IIb relative to Pit1 or Pit2. Selective inhibition of NaPi-IIb means, for example, the following situation: in this case, the 50% phosphate uptake inhibition concentration (IC 50 ) ratio (IC 50 [Pit1] / IC 50 [NaPi-IIb]) and / or (IC 50 [Pit2] / IC 50 [NaPi-IIb]) is 10 or greater, 100 or greater or 500 or greater.

[0350] In one aspect of the invention, the compound that inhibits phosphate transporters is a compound having an IC 50 [Pit1] / IC 50 [NaPi-IIb] and / or IC 50 [Pit2] / IC 50 [NaPi-IIb] (which is 10 or more, 100 or more, or 500 or more).

[0351] In one aspect of the present invention, the compound used as an active ingredient in the pharmaceutical composition may be a salt thereof or a solvate thereof. The salt of the compound described herein may be a pharmaceutically acceptable salt. The salt of the compound described herein includes acid addition salts and base addition salts. Examples of acid addition salts include hydrochlorides, hydrobromides, hydroiodides, phosphates, phosphonates, sulfates, etc.; sulfonates such as methanesulfonates, ethanesulfonates, benzenesulfonates, and p-toluenesulfonates; and carboxylates such as acetates, citrates, malates, tartrates, succinates, salicylates, maleates, fumarates, benzoates, malonates, glycolates, oxalates, glucuronates, adipates, glutarates, ketoglutarates, and hippurates. Examples of base addition salts include alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as magnesium and calcium salts; ammonium salts such as ammonium, alkylammonium, dialkylammonium, trialkylammonium and tetraalkylammonium salts; and amino acid salts such as lysine, arginine, glycine, valine, threonine, serine, proline and alanine salts. These salts are produced by contacting the compound with an acid or base that can be used to make a pharmaceutical product.

[0352] In one aspect of the present invention, solvate refers to a solvate in which a compound forms a single molecule assembly together with a solvent, and is not particularly limited, as long as the solvate is formed by a solvent (the solvent is acceptable to be taken in together with the drug administration). The specific example of solvate not only includes hydrates, alcohol hydrates (such as ethanol hydrates, methanol hydrates, 1-propanol hydrates, 2-propanol hydrates, etc.), solvates formed by a single solvent such as dimethyl sulfoxide, but also includes solvates in which each molecule of the compound is formed by a variety of solvents, or solvates in which each molecule of the compound is formed by various types of solvents. When the solvent is water, the solvate is referred to as a hydrate.

[0353] Compounds described herein and salts thereof used as active ingredients in pharmaceutical compositions may exist as a variety of tautomers (e.g., keto form and enol form, imine form and enamine form, and mixtures thereof). Tautomers may exist in solution as mixtures of tautomers. In solid form, one tautomer is usually dominant. Although one tautomer may be described, the present invention also includes all tautomers of the compounds of the present invention. Compounds described herein, their salts, or solvates thereof include all of their stereoisomers (e.g., enantiomers, diastereomers (cis and trans geometric isomers)), racemates and other mixtures of isomers. Compounds may have, for example, one or more asymmetric points, and the present invention includes racemic mixtures, diastereomeric mixtures, and enantiomers of such compounds.

[0354] The compounds described herein used as active ingredients in pharmaceutical compositions may contain non-naturally occurring percentages of isotope atoms in one or more atoms constituting such compounds. Compounds that are substituted with isotopes in a ratio different from that of isotopes in nature (which is carried out by replacing any atom in the compound with an atom having the same atomic number (number of protons) and a different mass number (the sum of the number of protons and the number of neutrons)), i.e., compounds labeled with isotope atoms, are also included in the present invention. Examples of isotope elements contained in the compounds herein include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, and they include: 2 H. 3 H. 13 C. 14 C. 15 N. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 Cl, etc. Compounds labeled with isotopic atoms can be used as therapeutic agents or preventive agents, research reagents (e.g., assay reagents) and diagnostic agents (e.g., in vivo imaging diagnosis). For compounds as used herein, all compounds containing radioactive or non-radioactive isotope elements in any proportion are encompassed within the scope of the present invention. Compounds labeled with isotopic atoms can be produced by using reagents or solvents containing corresponding isotopic atoms in a manner similar to the method for producing unlabeled compounds.

[0355] The compounds described herein used as active ingredients in pharmaceutical compositions may be in the form of prodrugs. As used herein, "prodrugs" means derivatives of compounds described herein, which are used as active ingredients in pharmaceutical compositions by enzymatic or non-enzymatic degradation after administration under physiological conditions to convert into compounds or pharmaceutically acceptable salts thereof. When administered to a patient, the prodrug may be inactive, but is converted in vivo and exists as a compound having inhibitory activity against phosphate transporters.

[0356] For example, the prodrug is converted to the desired drug form at a specific pH or by the action of an enzyme. Typical prodrugs are compounds that generate free acids in vivo and compounds with hydrolyzable ester groups. Examples of such hydrolyzable ester groups include, but are not limited to, groups represented by the formula -COORx, wherein Rx is selected from C 1-4 Alkyl, C 2-7 Alkanoyloxymethyl, 1-(C 4-9 Alkanoyloxy)ethyl, 1-methyl-1-(C 510 Alkanoyloxy)-ethyl, (C 3-6 alkoxy)carbonyloxymethyl, 1-[(C4-7 alkoxy)carbonyloxy]ethyl, 1-methyl-1-[(C 5-8 alkyloxy)carbonyloxy]ethyl, N-[(C 3-9 alkoxy)carbonyl]aminomethyl, 1-(N-[(C 4-10 alkyloxy)carbonyl]amino)ethyl, 3-phthalyl, 4-crotonyl, γ-butyrolactone-4-yl, [N,N-di(C 1-2 alkyl)amino]C 2-3 Alkyl (e.g., N,N-dimethylaminoethyl), (carbamoyl) C 1-2 Alkyl, [N,N-di(C 1-2 alkyl)carbamoyl]C 1-2 Alkyl, (piperidino) C 2-3 Alkyl, (pyrrolidino) C 2-3 Alkyl or (morpholino)C 2-3 alkyl.

[0357] The subject to which the compounds, salts or solvates of the present disclosure are administered is an animal, preferably a mammal (e.g., mouse, rat, rabbit, dog, monkey (e.g., cynomolgus monkey) or human), particularly preferably a human. The human may be an adult (who is 18 years of age or older) or a child (under 18 years of age). The child is preferably, for example, 6 months or older.

[0358] In one aspect of the invention, a pharmaceutical composition comprising a compound that inhibits phosphate transporters can be used to prevent or treat cystic diseases or inhibit the formation or expansion of cysts. Examples of cystic diseases include cystic kidney disease, polycystic liver disease, cystic lung disease, and pancreatic cysts. The formation or expansion of cysts can occur, for example, in the kidney, liver, lung, or pancreas.

[0359] In one aspect of the invention, a pharmaceutical composition comprising a compound that inhibits phosphate transporters can be used to treat or prevent cystic kidney disease, including polycystic kidney disease, autosomal dominant polycystic kidney disease (ADPKD), etc., or to inhibit the formation or expansion of renal cysts. In addition to the above diseases, cystic kidney disease also includes, for example, multiple simple renal cysts, renal tubular acidosis, polycystic kidney, multicystic dysplastic kidney, multilocular renal cysts, renal medullary cystic disease, juvenile nephronophthisis, acquired renal cystic disease, and autosomal recessive polycystic kidney disease.

[0360] Polycystic kidney disease can be diagnosed, for example, by confirming the presence of multiple cysts in bilateral kidneys by imaging (such as CT, MRI or ultrasound tomography). In one aspect of the invention, polycystic kidney disease is diagnosed when three or more or five or more cysts are confirmed in each kidney on both sides.

[0361] In one aspect of the invention, "effective amount" means a dosage of a phosphate transporter inhibitor that is effective in treating or preventing a disease, particularly a cystic disease in an individual. Examples of effective amounts include, but are not limited to, a dosage in the range of 0.0001 mg / kg body weight / dose to 1000 mg / kg body weight / dose, preferably 0.001 mg / kg body weight / dose to 100 mg / kg body weight / dose, and further preferably 0.01 mg / kg body weight / dose to 50 mg / kg body weight / dose, for example, once every 1 week to 10 weeks, preferably once every 1 week to 8 weeks, and even more preferably once every 1 week to 4 weeks.

[0362] In one aspect of the present invention, the following aspects are provided.

[0363] (1) A compound that inhibits NaPi-IIb for use in treating or preventing cystic kidney disease in a mammal, the compound being selected from the group consisting of (i) to (iii) below:

[0364] (i) low molecular weight compounds having a molecular weight of 2000 g / mol or less;

[0365] (ii) anti-NaPi-IIb antibodies; and

[0366] (iii) a polynucleotide selected from the group consisting of an antisense molecule, a microRNA, and a small interfering RNA (siRNA).

[0367] (2) A compound that inhibits NaPi-IIb, which is used for inhibiting renal cyst formation in mammals, the compound being selected from the group consisting of the following (i) to (iii):

[0368] (i) low molecular weight compounds having a molecular weight of 2000 g / mol or less;

[0369] lii) anti-NaPi-IIb antibody; and

[0370] (iii) a polynucleotide selected from the group consisting of an antisense molecule, a microRNA, and a small interfering RNA (siRNA).

[0371] In one aspect of the invention, a method for predicting the effect of treatment with an agent in a patient with a cystic disease is provided, the method comprising confirming whether NaPi-IIb is expressed in cells collected from an organ of a patient with a cystic disease in which a cyst has formed. In this context, the agent is an inhibitor of NaPi-IIb.

[0372] In one aspect of the present invention, a method for predicting the effect of treatment with a pharmaceutical agent in a patient with cystic kidney disease is provided, the method comprising confirming whether NaPi-IIb is expressed in renal cells collected from patients with cystic kidney disease. In this article, the pharmaceutical agent is an inhibitor of NaPi-IIb. As renal cells collected from patients with cystic kidney disease, cells obtained, for example, by renal biopsy can be used, and specifically, cells obtained by needle biopsy or open renal biopsy under ultrasound guidance can be used.

[0373] In another aspect of the invention, a pharmaceutical composition comprising a compound that inhibits phosphate transporters as an active ingredient is provided for inhibiting renal cyst formation. Renal cysts can be diagnosed, for example, by confirming them by image examinations such as ultrasound, CT or MRI. In one aspect of the invention, the pharmaceutical composition is used for subjects with a risk of autosomal dominant polycystic kidney disease until the onset of cystic kidney disease. In one aspect of the invention, the pharmaceutical composition is used to inhibit further renal cyst formation, i.e., for inhibiting the progression of the disease, even after the onset of cystic kidney disease.

[0374] In one aspect of the invention, a compound that inhibits phosphate transporters or a composition comprising a compound is administered to a subject with confirmed familial occurrence of autosomal dominant polycystic kidney disease. Here, familial occurrence is confirmed by the presence or absence of a patient in a parent, sibling, grandfather, grandmother, uncle, aunt, cousin, etc. In one subject of the present invention, a compound that inhibits phosphate transporters is administered to a subject whose parents are a subject with chromosomal dominant polycystic kidney disease.

[0375] In one aspect of the invention, a compound that inhibits phosphate transporters or a composition comprising a compound is administered to a subject having a PKD1 or PKD2 deficiency. Here, a PKD1 or PKD2 deficiency can be confirmed in cells obtained from a subject by methods known to those skilled in the art. In one aspect of the invention, the subject has a PKD1 deficiency.

[0376] The age of the subject to whom the compound that inhibits phosphate transporters or the composition comprising the compound is administered is not particularly limited, and can be, for example, 15 years of age or less, and 16 years of age or more, 20 years of age or more, 25 years of age or more, 30 years of age or more, 35 years of age or more, 40 years of age or more, 45 years of age or more, 50 years of age or more, 60 years of age or more, or 70 years of age or more. In one aspect of the invention, the compound or composition is administered to a subject 30 years of age or more.

[0377] Cystic diseases described herein or the formation or expansion of cysts can be diagnosed or confirmed by inspection methods known to those skilled in the art (such as CT, MRI or ultrasonic tomography). In one aspect of the invention, the compound that inhibits phosphate transporters or the composition comprising the compound is applied to a subject confirmed to have one or two or more cysts in a specific organ (e.g., kidney, liver, lung or pancreas). In one aspect of the invention, the subject administered is a subject confirmed to have one or two or more cysts in the kidney. Specifically, the compound or composition is applied to a subject confirmed to have three or more cysts in each kidney on both sides by CT, MRI or ultrasonic tomography.

[0378] In one aspect of the invention, a method for screening a compound for treating or preventing a disease selected from cystic disease, polycystic liver disease, cystic lung disease or / and pancreatic cysts is provided, the method comprising measuring the inhibitory activity against phosphate transporters. In one aspect of the invention, a method for screening a compound for inhibiting cyst formation or cyst expansion in an organ of a mammal is also provided, the method comprising measuring the inhibitory activity against phosphate transporters. These screening methods are sometimes referred to as "methods for screening compounds" hereinafter.

[0379] The compounds that inhibit phosphate transporters screened in the method for screening the above-mentioned compounds can be used to provide a pharmaceutical composition for treating or preventing a disease involving phosphate transporters, which disease is selected from cystic disease, polycystic liver disease, cystic lung disease, or / and pancreatic cysts and cystic kidney disease, and the pharmaceutical composition contains a compound that inhibits phosphate transporters as an active ingredient.

[0380] The test compound used in the method of screening the compound used as an active ingredient in the pharmaceutical composition is not particularly limited, and its example includes at least one selected from the group consisting of the low molecular weight compound, polypeptide and polynucleotide listed above, as a compound that inhibits the above-mentioned phosphate transporter. More specific examples of test compounds include synthetic low molecular weight compound libraries, gene library expression products, peptide libraries, siRNA, antibodies, bacterial release materials, extracts and culture supernatants of cells (microorganisms, plant cells, animal cells), purified or partially purified polypeptides, marine organisms, extracts from plants or animals, and phage random peptide display libraries. The test compound can also be a derivative of a known phosphate transporter.

[0381] The method for screening the above-mentioned compounds may include: selecting a compound having inhibitory activity against a phosphate transporter. The inhibitory activity against a phosphate transporter in the method for screening the above-mentioned compounds may be measured by a known method. The index for confirming the inhibitory activity may be a 50% phosphate uptake inhibition concentration (IC ) in a cell expressing a phosphate transporter as described above.50 ).

[0382] In one aspect of the present invention, the following screening method is provided.

[0383] (1) A method for screening a compound for treating or preventing cystic kidney disease in a mammal, the method comprising measuring an inhibitory activity against NaPi-IIb, and selecting a compound having an inhibitory activity against NaPi-IIb.

[0384] (2) In one aspect of the present invention, a method for screening a compound for inhibiting cyst formation or cyst expansion in an organ of a mammal comprises measuring the inhibitory activity against NaPi-IIb, and selecting a compound having the inhibitory activity against NaPi-IIb.

[0385] (3) In one aspect of the present invention, a method for screening a compound for inhibiting cyst formation or cyst expansion in the kidney of a mammal comprises measuring the inhibitory activity against NaPi-IIb, and selecting a compound having inhibitory activity against NaPi-IIb.

[0386] Hereinafter, the present invention will be described in more detail using examples, but the present invention is not limited to these examples. All starting materials and reagents were obtained from commercial suppliers or synthesized by known methods.

[0387] Examples

[0388] Pharmacology Test Examples

[0389] Test Example 1: Expression of human NaPi-IIb, human PiT1 or human PiT2 in cells 33 Evaluation of PO4 uptake inhibition

[0390] For transient expression, human NaPi-IIb expression plasmid, human PiT1 expression plasmid, human PiT2 expression plasmid and Fugene HD Transfection (Promega Corporation) were added to CHO cells using a 96-well plate, and the plate was cultured in a CO2 incubator for 16 hours. The medium was replaced with buffer A (145 mM choline chloride, 3 mM KCl, 1 mM CaCl2, 0.5 mM MgCl2, 5 mM glucose, 5 mM MES (pH 6.5)), and then replaced with buffer B (145 mM NaCl, 3 mM KCl, 1 mM CaCl2, 0.5 mM MgCl2, 5 mM glucose, 5 mM MES (pH 6.5)), to which the test compound was added at a final concentration of 0.01, 0.03, 0.1, 0.3, 1, 3, 10 or 30 μM, to which buffer A with DMSO was added, or to which buffer B with DMSO was added. After a certain period of time, add 1 / 20 of the amount of 33 PO4 (PerkinElmer Japan GK) buffer A and react at room temperature. After washing with ice-cold buffer A, liquid scintillant (MicroScint TM -20, item number 6013621, PerkinElmer Japan GK) and measured using a luciferase reporter analyzer (Top Count) (Top CountNXT, PerkinElmer Japan GK) 33 PO4 uptake. The inhibition rate is determined by the following formula. Here, the "certain time" is set to 10 minutes. The phrase "add 1 / 20 of the amount of 33 PO4 (PerkinElmer Japan GK)” means “adding a buffer containing 1 / 20 of the solution volume of the culture medium”. 33 PO4 (PerkinElmer Japan GK) buffer A".

[0391] Inhibition rate (%) = (1-(the number of wells treated with buffer B to which the test compound was added) 33 PO4 uptake - wells treated with buffer A with DMSO added 33 PO4 uptake) / (DMSO-added wells treated with buffer B 33 PO4 uptake - wells treated with buffer A with DMSO added 33 PO4)) x 100

[0392] 50% in cells expressing human NaPi-IIb, human PiT1, and human PiT2 33PO4 uptake inhibition concentration (IC 50 ) (μM) was calculated from a straight line passing through two points sandwiching a 50% inhibition rate. The results are shown in Table 1. It should be noted that Compound 1 and Compound 2 were not measured against human PiT1 and human PiT2, which are indicated as "-" in Table 1.

[0393] [Table 1]

[0394] [Table 1: Results of Test Example 1]

[0395]

[0396] The results of the above tests confirmed that each test compound had an inhibitory effect on human NaPi-IIb expressing cells. 33 Inhibitory effect on PO4 uptake.

[0397] Test Example 2: Evaluation of NaPi-IIb expression levels in renal tissues of human ADPKD patients

[0398] NaPi-IIb mRNA levels in renal tissue of human ADPKD patients were evaluated using Visium spatial gene expression (10xGenomics). Tissue containing cysts was excised from renal tissue removed from ADPKD patients, and frozen blocks were prepared by OCT embedding. The frozen blocks were sliced ​​and placed on slides for Visium gene expression, and HE staining was performed. After obtaining the HE staining image, cDNA was generated, and NovaSeq6000 (Illumina, Inc) was used to perform sequence analysis of the short read sequence library on the cDNA. The results of the sequence analysis are reflected in the HE staining image using Loupe Browser (10x Genomics). The number of each gene in each spot calculated by the sequence analysis is corrected by the number of housekeeping genes and the number of nucleic acids in each spot to obtain the value of the expression level of each gene. HE staining images and NaPi-IIb expression levels are shown in Figure 1. Figures 1a to 1f In Figure 1, the gray scale bar shows the NaPi-IIb expression level, where 4.0 indicates log22 4.0 , and 0.0 indicates log22 0.0 .

[0399] As a result of the above-mentioned tests, high expression of NaPi-IIb was confirmed in renal tissues of human ADPKD patients.

[0400] Test Example 3: Evaluation of NaPi-IIb expression level in kidney tissue of PKD model mice

[0401] The NaPi-IIb mRNA level in the renal tissue of PC1 conditional knockout mice (obtained by the passage breeding of those mice produced at Lieden University), DBA / 2FG-pcy mice (hereinafter referred to as pcy mice) (KYUDO CO., LTD.) and C57BL / 6J mice (CLEA Japan, Inc.) was confirmed using Visium spatial gene expression (10x Genomics). From the 21st day after birth, tamoxifen was orally administered to PC1 conditional knockout mice at a dosage of 3 mg / kg for 3 days, and the kidneys were removed 16 weeks after administration. For DBA / 2FG-pcy and C57BL / 6J mice, kidneys were removed from 9-week-old individuals. Subsequent procedures were the same as in Test Example 2. Figure 2a to Figure 2c Figure 2 is a graph showing the HE staining images of renal tissues of PC1 conditional knockout mice, pcy mice, and C57BL / 6J mice and the expression level of NaPi-IIb. Figure 2a to Figure 2c The gray scale bar shows the NaPi-IIb expression level, where 4.0 indicates log22 4.0 , and 0.0 indicates log22 0.0 .

[0402] As a result of the above tests, high expression of NaPi-IIb was confirmed in kidney tissue of the mouse PKD model.

[0403] Test Example 4: Evaluation of the inhibitory effect on kidney volume increase and renal function decrease in pcy mice

[0404] pcy mice (a naturally occurring PKD model) were used to evaluate the effects of tolvaptan and Compound 4 in Test Example 1 on (a) kidney volume, (b) blood urea nitrogen (UN) concentration, (c) body weight, and (d) urine volume in pcy mice.

[0405] The pcy mice (5 weeks old at the beginning of the test) were grouped into 3 groups, 13 mice in each group. Compound 4 or tolvaptan was applied to each group in the test compound administration group. The application period was 5 weeks. Compound 4 was administered subcutaneously once a day, and tolvaptan was administered subcutaneously once a week. Compound 4 was administered at 33mg / kg to 40mg / kg per dose, and tolvaptan was administered at 25mg / kg to 30mg / kg per dose. After being dissolved in 50% DMSO / 50% glycerol, compound 4 and tolvaptan were administered. A group of parent strain mice was provided as a normal control group (normal control) (N=7). 50% DMSO / 50% glycerol was administered to the normal control group and vehicle group of pcy mice at 1mL / kg.

[0406] Five weeks after the start of administration of the test compound, the left kidney volume (kidney volume (mL)) of the mice was calculated using echography by the following formula: Figure 3a shown.

[0407] Kidney volume (mL) = π x long diameter (mm) x short diameter (mm) x short diameter (mm) x 1000 / 6

[0408] After that, blood was collected from the abdominal vein, plasma was collected, and euthanasia was performed. Blood urea nitrogen (UN) concentration (plasma UN (mg / L)) was measured using L-type Waco UN (Fujifilm Wako Pure Chemical Corporation), as Figure 3b shown.

[0409] In addition, after the start of administration of the test compound, the body weight (body weight (g)) of the mice was measured every 7 days. Figure 3c In addition, the urine volume (urine volume (mL / day)) was calculated based on the specific gravity of urine 5 weeks after the start of administration of the test compound and the measured weight, as shown in FIG. Figure 3d shown.

[0410] The results of the above tests confirmed that Compound 4 has the same degree of inhibitory effect on kidney volume increase and kidney function decrease as tolvaptan. It also showed that Compound 4 caused less weight loss and no increase in urine volume compared to tolvaptan.

[0411] Test Example 5: Evaluation of the effect of inhibiting three-dimensional cyst formation using primary cells from kidney tissue of human ADPKD patients

[0412] Primary cells are isolated from the kidney tissue of human ADPKD patients. In two dimensions, the isolated cells are cultured for 2 days using DMEM / F-12 (Thermo Fisher Scientific, Inc.) supplemented with 10% FBS. Subsequently, 3D culture is performed using 3D Ready Atelocollagen (KOKEN CO., LTD.) for 7 days. During the three-dimensional culture, 50 μM forskolin (Sigma-Aldrich Co.LLC) and ITS liquid culture medium supplement (Sigma-Aldrich Co.LLC) are added to some holes as stimulants to form cysts, and test compounds are added with a final concentration of 30 μM. Test compounds are also added to other holes with a final concentration of 30 μM. After 7 days of three-dimensional culture, it was fixed with 4% paraformaldehyde (Thermo Fisher Scientific, Inc.), and nucleic acid staining and cell membrane staining were performed with Hoechst33342 (Thermo Fisher Scientific, Inc.) and CellLight Plasma Membrane-RFP, BacMam2.0 (Thermo Fisher Scientific, Inc.). Three-dimensional imaging and volume analysis were performed using Operetta CLS and image analysis software Harmony (PerkinElmer Japan GK). The inhibition rate was determined by the following formula.

[0413] Inhibition rate (%) = (1-(volume of wells with added stimulants and test compounds-volume of wells with added stimulants and no test compounds) / (volume of wells with added stimulants and no test compounds-volume of wells without added stimulants and test compounds)) x 100

[0414] Figure 4 The three-dimensional images are shown for (a) wells without addition of stimulants and compound 4, (b) wells with addition of stimulants and without addition of compound 4, and (c) wells with addition of stimulants and compound 4. Table 2 shows the average inhibition rate of each test compound (N=3).

[0415] [Table 2]

[0416] [Table 2: Results of Test Example 5]

[0417] Compound No. Inhibition rate (%) 1 98.2 2 100.0 3 100.0 4 94.4

[0418] The results of the above tests confirmed the inhibitory effect of each test compound on high cyst formation.

[0419] Test Example 6: Evaluation of the inhibitory effect on kidney volume increase and kidney function decrease in PC1 conditional knockout mice

[0420] PC1 conditional knockout mice (PKD model) were used to evaluate the effects of tolvaptan and Compound 4 in Test Example 1 on (a) kidney volume, (b) body weight, and (c) urine volume in PC1 conditional knockout mice.

[0421] Starting from the 21st day after birth, tamoxifen was orally administered to PC1 conditional knockout mice at a dose of 3mg / kg for 3 days. PC1 conditional knockout mice (5 weeks old at the beginning of this test) were grouped into 3 groups, 15 mice in each group. Compound 4 or tolvaptan was applied to the test compound administration group as a single agent. The administration period was 16 weeks, and it was subcutaneously administered once a day. Compound 4 was administered at 33mg / kg to 40mg / kg per dose, and tolvaptan was administered at 25mg / kg to 30mg / kg per dose. After being dissolved in 50% DMSO / 50% glycerol, compound 4 and tolvaptan were administered. A group of mice to which tamoxifen was not administered was provided as a normal control group (normal control) (N=7). 50% DMSO / 50% glycerol was applied to the normal control group and vehicle group of PC1 conditional knockout mice at 1mL / kg.

[0422] 16 weeks after the start of administration of the test compound, the left kidney volume (kidney volume (mL)) of the mice was calculated by the following formula using echography. Figure 5a Shown in.

[0423] Kidney volume (mL) = π x long diameter (mm) x short diameter (mm) x short diameter (mm) x 1000 / 6

[0424] After that, euthanasia was performed. In addition, the body weight (body weight (g)) of the mice was measured every 7 days after the start of administration of the test compound. Figure 5b In addition, the urine volume (urine volume (mL / day)) was calculated based on the specific gravity of urine 16 weeks after the start of administration of the test compound and the measured weight. The results are shown in Figure 5c Shown in.

[0425] The results of the above tests confirmed the inhibitory effect of compound 4 on the increase in renal volume and the decrease in renal function. It also showed that compound 4 caused less weight loss and no increase in urine volume compared to tolvaptan.

Claims

1. A pharmaceutical composition comprising a compound that inhibits phosphate transporters as an active ingredient, wherein the pharmaceutical composition is used for treating or preventing cystic diseases.

2. A pharmaceutical composition comprising a compound that inhibits phosphate transporters as an active ingredient, wherein the pharmaceutical composition is used for inhibiting the formation or expansion of cysts. 3 . The pharmaceutical composition according to claim 1 , wherein the phosphate transporter is at least one selected from the group consisting of NaPi-IIa, NaPi-IIb and NaPi-IIc.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the phosphate transporter is NaPi-IIb.

5. The pharmaceutical composition according to any one of claims 1, 3 and 4, wherein the cystic disease is a disease involving NaPi-IIb.

6. The pharmaceutical composition according to any one of claims 2 to 4, wherein the cyst is a cyst involving NaPi-IIb. 7 . The pharmaceutical composition according to claim 1 , wherein the compound is at least one selected from the group consisting of low molecular weight compounds, polypeptides, and polynucleotides.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the compound is a compound selected from the group consisting of compounds represented by Formula 1 to Formula 11: or a salt thereof, or a solvate thereof.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the cystic disease is selected from the group consisting of cystic kidney disease, polycystic liver disease, cystic lung disease and pancreatic cysts.

10. The pharmaceutical composition according to any one of claims 2 to 4 and 6 to 9, wherein the cyst is a cyst formed or expanded in the kidney, liver, lung or pancreas.

11. The pharmaceutical composition according to any one of claims 1 to 10, for use in the treatment or prevention of cystic kidney disease.

12. The pharmaceutical composition according to any one of claims 1 to 11, for use in treating or preventing polycystic kidney disease.

13. A method for predicting the effect of treatment with a pharmaceutical agent in a patient suffering from a cystic disease, the method comprising: The expression of NaPi-IIb was confirmed in cells collected from organs of patients who had developed cysts; as well as The patient in whom the expression is confirmed is determined to be a patient who will obtain a therapeutic effect, and the drug is determined to be an inhibitor of NaPi-IIb.

14. A method for screening a compound for treating or preventing a disease selected from cystic kidney disease, polycystic liver disease, cystic lung disease and pancreatic cysts, the method comprising measuring inhibitory activity against a phosphate transporter.

15. A method for screening a compound for inhibiting cyst formation or expansion in an organ of a mammal, the method comprising measuring inhibitory activity against a phosphate transporter.

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