Pharmaceutical composition for treating or preventing cystic disease

Abstract

The present invention provides a pharmaceutical composition which is for use in the treatment or prevention cystic disease and which comprises, as an active component, a compound that inhibits a phosphate transporter.

Description

Pharmaceutical compositions for treating or preventing cystic diseases

[0001] The present invention relates to a pharmaceutical composition for treating or preventing cystic diseases, which comprises as an active ingredient a compound that inhibits a phosphate transporter. 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.

[0002] Cystic diseases include cystic kidney disease, pancreatic cystic disease, cystic liver, cystic lung disease, and pancreatic cysts. Polycystic kidney disease (PKD), one of the cystic diseases, is a hereditary disease in which numerous cysts form in the kidneys. The growth of cysts leads to an increase in kidney volume and a decline in renal function (Non-Patent Document 1). To date, tolvaptan is the only drug used to treat PKD, but side effects (hepatotoxicity, polyuria, etc.) have been reported (Non-Patent Document 3). Therefore, the development of a new PKD therapeutic agent that overcomes these problems is desired.

[0003] Phosphorus is present in all cells, accounts for 1% of body weight, and plays an essential role in maintaining life, including cellular energy metabolism. Blood phosphorus concentration is regulated to a constant level by absorption from the digestive tract, excretion from the kidney, bone formation, and bone resorption. Phosphorus absorption in the digestive tract is primarily mediated by the phosphate transporter NaPi-IIb (SLC34A2) (Non-Patent Documents 4 and 5). Blood phosphorus is filtered in the glomerulus of the kidney, and the required amount is reabsorbed in the renal tubules primarily by NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) (Non-Patent Documents 4 and 6). The kidneys play a crucial role in regulating phosphorus in the body. In patients with end-stage renal failure and dialysis patients with impaired renal function, phosphorus accumulates in the body, leading to elevated blood phosphorus levels, or hyperphosphatemia.

[0004] It is believed that inhibiting NaPi-IIb, which plays a major role in phosphorus absorption in the digestive tract, can suppress phosphorus absorption in the digestive tract, similar to the case of phosphorus binders, and reduce the phosphorus concentration in the blood (Non-Patent Documents 5 and 7). NaPi-IIb inhibitors have been reported so far (Patent Documents 1 to 6, Non-Patent Documents 8 and 9).

[0005] WO2012 / 006475WO2011 / 136269WO2008 / 051980WO2013 / 062065WO2016 / 039458WO2014 / 142273

[0006] Vervloe, M., Nat Rev Nephrol. 2019 Feb;15(2):70-72Wu, M. et al., Kidney Dis 2016;2:128-135Blair, HA, et al., Drugs. 2019 Feb;79(3):303-313Miyamoto, K. et al., J Pharm Sci. 2011 Sep; 100(9): 3719-30.Sabbagh, Y. et al., J Am Soc Nephrol. 2009 Nov; 20(11): 2348-58.Murer, H. et al., Pflugers Arch.2004 Feb;447(5):763-7.Ohi, A. et al., Am J Physiol Renal Physiol. 2011 Nov; 301(5): F1105-13. Tsuboi, Y., et al., Kidney International (2020) 98, 343-354;Maruyama, S. et al., Kidney International Reports (2021) 6, 675-684Dixon EE., J Am Soc Nephrol. 2022 Feb;33(2):279-289.

[0007] An object of the present invention is to provide a medicament for treating or preventing cystic diseases.

[0008] In view of the above problems, the present inventors have conducted studies and found that phosphate transporters are highly expressed in the kidney tissues of patients with cystic diseases. Furthermore, the present inventors have found that compounds that inhibit phosphate transporters have excellent effects in the treatment or prevention of cystic diseases, and have completed the present invention. This specification includes the disclosure of the following inventions.

[0009] [A-1] A pharmaceutical composition for use in the treatment or prevention of cystic diseases, comprising as an active ingredient a compound that inhibits a phosphate transporter. [A-2] A pharmaceutical composition for suppressing the formation or expansion of cysts, comprising as an active ingredient a compound that inhibits a phosphate transporter.

[0010] [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.

[0011] [A-4] The pharmaceutical composition according to any one of [A-1] to [A-3], wherein the phosphate transporter is NaPi-IIb. [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 affected by the cystic disease.

[0012] [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 associated with NaPi-IIb.

[0013] [A-7] The pharmaceutical composition according to any one of [A-2] to [A-4], wherein NaPi-IIb is highly expressed in the cells of the cyst.

[0014] [A-8] The pharmaceutical composition according to any one of [A-2] to [A-4] and [A-7], wherein the cyst is a cyst associated with NaPi-IIb. [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 a low molecular weight compound, a polypeptide, and a polynucleotide.

[0015] [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. [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.

[0016] [A-12] The pharmaceutical composition according to any one of [A-1] to [A-9], wherein the compound is a polypeptide including an antibody. [A-13] The pharmaceutical composition according to any one of [A-1] to [A-9], wherein the compound is an anti-phosphate transporter antibody.

[0017] [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 an anti-NaPi-IIa antibody, an anti-NaPi-IIb antibody, and an anti-NaPi-IIc antibody. [A-15] The pharmaceutical composition according to any one of [A-1] to [A-9], wherein the compound is an anti-NaPi-IIb antibody.

[0018] [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 a ribozyme, an antisense molecule, an inhibitor oligonucleotide, an aptamer, a microRNA, and a small interfering RNA (siRNA).

[0019] [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).

[0020] [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): (i) a low-molecular-weight compound having a molecular weight of 2000 g / mol or less, (ii) an anti-NaPi-IIb antibody, and (iii) a polynucleotide selected from the group consisting of an antisense molecule, a microRNA, and a small interfering RNA (siRNA).

[0021] [A-19] The pharmaceutical composition according to any one of [A-1] to [A-18], wherein the compound is administered parenterally. [A-20] The pharmaceutical composition according to any one of [A-1] to [A-11] and [A-18], wherein the compound is administered orally.

[0022] [A-21] The pharmaceutical composition according to any one of [A-1] to [A-20], wherein the compound is a compound that selectively inhibits NaPi-IIb among the phosphate transporters.

[0023] [A-22] The compound is a compound that selectively inhibits NaPi-IIb among the phosphate transporters, and the concentration at which phosphate uptake in cells expressing NaPi-IIb or Pit1 is inhibited by 50% (IC ５０ ) ratio (IC ５０ [Pit 1] / IC ５０ The pharmaceutical composition according to any one of [A-1] to [A-21], wherein the saturation index (saturation index [NaPi-IIb]) is 10 or more.

[0024] [A-23] The compound is a compound that selectively inhibits NaPi-IIb among the phosphate transporters, and the concentration at which phosphate uptake in cells expressing NaPi-IIb or Pit2 is inhibited by 50% (IC ５０ ) ratio (IC ５０ [Pit 2] / IC ５０ The pharmaceutical composition according to any one of [A-1] to [A-22], wherein the saturation index (saturation index [NaPi-IIb]) is 10 or more.

[0025] [A-24] The concentration of the compound that inhibits phosphate uptake by 50% in cells expressing a phosphate transporter (IC ５０ The pharmaceutical composition according to any one of [A-1] to [A-23], wherein the total amount of the hydroxybenzoates is 10 μg / mol or less.

[0026] [A-25] The concentration of the compound that inhibits phosphate uptake by 50% in cells expressing NaPi-IIb (IC ５０ The pharmaceutical composition according to any one of [A-1] to [A-24], wherein the total amount of the hydroxybenzoates is 5 μg / mol or less.

[0027] [A-26] The concentration of the compound that inhibits phosphate uptake by 50% in cells expressing human NaPi-IIb (IC ５０ The pharmaceutical composition according to any one of [A-1] to [A-25], wherein the total amount of the hydroxybenzoates is 1 μg / mol or less.

[0028] [A-27] The compound is represented by formula 1 to 11

[0029]

[0030]

[0031] The pharmaceutical composition according to any one of [A-1] to [A-26], which is a compound selected from the group consisting of compounds represented by the formula:

[0032] [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 the compounds represented by the above formulas 1 to 4, or a salt thereof, or a solvate thereof.

[0033] [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. [A-30] The pharmaceutical composition according to [A-29], wherein the mammal is a human.

[0034] [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 cysts. [A-32] The pharmaceutical composition according to any one of [A-2] to [A-30], wherein the cystic disease is accompanied by the formation or expansion of cysts in the kidney, liver, lung, or pancreas.

[0035] [A-33] The pharmaceutical composition according to any one of [A-1] to [A-32], for inhibiting a phosphate transporter expressed in the kidney, liver, lung, or pancreas. [A-34] The pharmaceutical composition according to any one of [A-1] to [A-33], for use in the treatment or prevention of cystic kidney disease.

[0036] [A-35] The pharmaceutical composition according to any one of [A-1] to [A-34], for use in treating or preventing polycystic kidney disease. [A-36] The pharmaceutical composition according to [A-35], wherein the polycystic kidney disease is autosomal dominant polycystic kidney disease. [A-37] The pharmaceutical composition according to any one of [A-1] to [A-36], for use in suppressing the formation or expansion of renal cysts.

[0037] [B-1] A method for treating or preventing a cystic disease, the method comprising administering an effective amount of a compound that inhibits a phosphate transporter to a subject in need of such treatment or prevention. [B-2] A method for inhibiting the formation or expansion of cysts, the method comprising administering an effective amount of a compound that inhibits a phosphate transporter to a subject.

[0038] [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.

[0039] [B-4] The method according to any one of [B-1] to [B-3], wherein the phosphate transporter is NaPi-IIb. [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 affected by the cystic disease.

[0040] [B-6] The method according to any one of [B-1] and [B-3] to [B-5], wherein the cystic disease is a disease associated with NaPi-IIb.

[0041] [B-7] The method according to any one of [B-2] to [B-4], wherein NaPi-IIb is highly expressed in the cells of the cyst.

[0042] [B-8] The method according to any one of [B-2] to [B-4] and [B-7], wherein the cyst is a cyst associated with NaPi-IIb. [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 a low molecular weight compound, a polypeptide, and a polynucleotide.

[0043] [B-10] The method according to any one of [B-1] to [B-9], wherein the compound is a low molecular weight compound having a molecular weight of 2000 g / mol or less. [B-11] The method according to any one of [B-1] to [B-9], wherein the compound is a low molecular weight compound having a molecular weight of 1000 g / mol or less.

[0044] [B-12] The method according to any one of [B-1] to [B-9], wherein the compound is a polypeptide including an antibody. [B-13] The method according to any one of [B-1] to [B-9], wherein the compound is an anti-phosphate transporter antibody.

[0045] [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 an anti-NaPi-IIa antibody, an anti-NaPi-IIb antibody, and an anti-NaPi-IIc antibody. [B-15] The method according to any one of [B-1] to [B-9], wherein the compound is an anti-NaPi-IIb antibody.

[0046] [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 a ribozyme, an antisense molecule, an inhibitor oligonucleotide, an aptamer, a microRNA, and a small interfering RNA (siRNA).

[0047] [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).

[0048] [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): (i) a low-molecular-weight compound having a molecular weight of 2000 g / mol or less, (ii) an anti-NaPi-IIb antibody, and (iii) a polynucleotide selected from the group consisting of an antisense molecule, a microRNA, and a small interfering RNA (siRNA).

[0049] [B-19] The method according to any one of [B-1] to [B-18], wherein the compound is administered parenterally. [B-20] The method according to any one of [B-1] to [B-11] and [B-18], wherein the compound is administered orally.

[0050] [B-21] The method according to any one of [B-1] to [B-20], wherein the compound is a compound that selectively inhibits NaPi-IIb among the phosphate transporters.

[0051] [B-22] The compound is a compound that selectively inhibits NaPi-IIb among the phosphate transporters, and the concentration at which phosphate uptake in cells expressing NaPi-IIb or Pit1 is inhibited by 50% (IC ５０ ) ratio (IC ５０ [Pit 1] / IC ５０ [NaPi-IIb]) is 10 or more.

[0052] [B-23] The compound selectively inhibits NaPi-IIb among the phosphate transporters, and ５０ The ratio of IC ５０ [Pit 2] / IC ５０ [NaPi-IIb]) is 10 or more.

[0053] [B-24] The concentration of the compound that inhibits phosphate uptake by 50% in cells expressing a phosphate transporter (IC ５０ The method according to any one of [B-1] to [B-23], wherein the value of the total number of nucleotides in ...

[0054] [B-25] IC of the inhibitory activity of the compound on human NaPi-IIb ５０ The method according to any one of [B-1] to [B-24], wherein the β-glucan is 5 μg / mol or less.

[0055] [B-26] IC of the inhibitory activity of the compound against human NaPi-IIb ５０ The method according to any one of [B-1] to [B-25], wherein the amount of the hydroxybenzoate is 1 μg / mol or less.

[0056] [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 the above formulas 1 to 11, or a salt thereof, or a solvate thereof.

[0057] [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 the above formulas 1 to 4, or a salt thereof, or a solvate thereof.

[0058] [B-29] The method according to any one of [B-1] to [B-28], wherein the subject is a mammal. [B-30] The method according to [B-29], wherein the mammal is a human.

[0059] [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. [B-32] The method according to any one of [B-2] to [B-30], wherein the cystic disease is accompanied by the formation or expansion of cysts in the kidney, liver, lung, or pancreas.

[0060] [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. [B-34] The method according to any one of [B-1] to [B-33], for use in the treatment or prevention of cystic kidney disease.

[0061] [B-35] The method according to any one of [B-1] to [B-34] for treating or preventing polycystic kidney disease. [B-36] The method according to [B-35], wherein the polycystic kidney disease is autosomal dominant polycystic kidney disease. [B-37] The method according to any one of [B-1] to [B-36] for inhibiting the formation or expansion of renal cysts.

[0062] [C-1] Use of a compound that inhibits a phosphate transporter in the manufacture of a medicament for treating or preventing cystic diseases. [C-2] Use of a compound that inhibits a phosphate transporter in the manufacture of a medicament for inhibiting the formation or growth of cysts.

[0063] [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.

[0064] [C-4] The use according to any one of [C-1] to [C-3], wherein the phosphate transporter is NaPi-IIb. [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 affected by the cystic disease.

[0065] [C-6] The use according to any one of [C-1] and [C-3] to [C-5], wherein the cystic disease is a disease associated with NaPi-IIb.

[0066] [C-7] The use according to any one of [C-2] to [C-4], wherein NaPi-IIb is highly expressed in the cells of the cyst.

[0067] [C-8] The use according to any one of [C-2] to [C-4] and [C-7], wherein the cyst is a cyst associated with NaPi-IIb. [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 a low molecular weight compound, a polypeptide, and a polynucleotide.

[0068] [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. [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.

[0069] [C-12] The use according to any one of [C-1] to [C-9], wherein the compound is a polypeptide including an antibody. [C-13] The use according to any one of [C-1] to [C-9], wherein the compound is an anti-phosphate transporter antibody.

[0070] [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 an anti-NaPi-IIa antibody, an anti-NaPi-IIb antibody, and an anti-NaPi-IIc antibody. [C-15] The use according to any one of [C-1] to [C-9], wherein the compound is an anti-NaPi-IIb antibody.

[0071] [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).

[0072] [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).

[0073] [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): (i) a low-molecular-weight compound having a molecular weight of 2000 g / mol or less, (ii) an anti-NaPi-IIb antibody, and (iii) a polynucleotide selected from the group consisting of an antisense molecule, a microRNA, and a small interfering RNA (siRNA).

[0074] [C-19] The use according to any one of [C-1] to [C-18], wherein the compound is administered parenterally. [C-20] The use according to any one of [C-1] to [C-11] and [C-18], wherein the compound is administered orally.

[0075] [C-21] The use according to any one of [C-1] to [C-20], wherein the compound is a compound that selectively inhibits NaPi-IIb among the phosphate transporters.

[0076] [C-22] The compound is a compound that selectively inhibits NaPi-IIb among the phosphate transporters, and the concentration at which phosphate uptake in cells expressing NaPi-IIb or Pit1 is inhibited by 50% (IC５０ ) ratio (IC ５０ [Pit 1] / IC ５０ The use according to any one of [C-1] to [C-21], wherein the saturation index (saturation index [NaPi-IIb]) is 10 or more.

[0077] [C-23] The compound selectively inhibits NaPi-IIb among the phosphate transporters, and ５０ The ratio of IC ５０ [Pit 2] / IC ５０ The use according to any one of [C-1] to [C-22], wherein the saturation index (saturation index [NaPi-IIb]) is 10 or more.

[0078] [C-24] The concentration of the compound that inhibits phosphate uptake by 50% in cells expressing a phosphate transporter (IC ５０ The use according to any one of [C-1] to [C-23], wherein the value of the total amount of the hydroxybenzoates is 10 μg / mol or less.

[0079] [C-25] IC of the inhibitory activity of the compound against human NaPi-IIb ５０ The use according to any one of [C-1] to [C-24], wherein the concentration of the α-glucan in the α-glucan is 5 μg / mol or less.

[0080] [C-26] IC of the inhibitory activity of the compound on human NaPi-IIb ５０ The use according to any one of [C-1] to [C-25], wherein the amount of the hydroxybenzoate is 1 μg / mol or less.

[0081] [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 the above formulas 1 to 11, or a salt thereof, or a solvate thereof.

[0082] [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 the compounds represented by the above formulas 1 to 4, or a salt thereof, or a solvate thereof.

[0083] [C-29] The use according to any one of [C-1] to [C-28], wherein the cystic disease is a disease in a mammal. [C-30] The use according to [C-29], wherein the mammal is a human.

[0084] [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, cystic lung disease, and pancreatic cysts. [C-32] The use according to any one of [C-2] to [C-30], wherein the cystic disease is accompanied by the formation or expansion of cysts in the kidney, liver, lung, or pancreas.

[0085] [C-33] Use of any of [C-1] to [C-32] for inhibiting a phosphate transporter expressed in the kidney, liver, lung, or pancreas. [C-34] Use of any of [C-1] to [C-33] for use in the treatment or prevention of cystic kidney disease.

[0086] [C-35] The use according to any one of [C-1] to [C-34] for use in the treatment or prevention of polycystic kidney disease. [C-36] The use according to [C-35], wherein the polycystic kidney disease is autosomal dominant polycystic kidney disease. [C-37] The use according to any one of [C-1] to [C-36] for use in suppressing the formation or expansion of renal cysts.

[0087] [D-1] A compound that inhibits a phosphate transporter for use in the treatment or prevention of cystic diseases. [D-2] A compound that inhibits a phosphate transporter for use in the inhibition of cyst formation or expansion.

[0088] [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.

[0089] [D-4] The compound according to any one of [D-1] to [D-3], wherein the phosphate transporter is NaPi-IIb. [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 affected by the cystic disease.

[0090] [D-6] The compound according to any one of [D-1] and [D-3] to [D-5], wherein the cystic disease is a disease associated with NaPi-IIb.

[0091] [D-7] The compound according to any one of [D-2] to [D-4], wherein NaPi-IIb is highly expressed in the cells of the cyst.

[0092] [D-8] The compound according to any one of [D-2] to [D-4] and [D-7], wherein the cyst is a cyst associated with NaPi-IIb. [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 a low molecular weight compound, a polypeptide, and a polynucleotide.

[0093] [D-10] The compound according to any one of [D-1] to [D-9], wherein the compound is a low molecular weight compound having a molecular weight of 2000 g / mol or less. [D-11] The compound according to any one of [D-1] to [D-9], wherein the compound is a low molecular weight compound having a molecular weight of 1000 g / mol or less.

[0094] [D-12] The compound according to any one of [D-1] to [D-9], wherein the compound is a polypeptide including an antibody. [D-13] The compound according to any one of [D-1] to [D-9], wherein the compound is an anti-phosphate transporter antibody.

[0095] [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 an anti-NaPi-IIa antibody, an anti-NaPi-IIb antibody, and an anti-NaPi-IIc antibody. [D-15] The compound according to any one of [D-1] to [D-9], wherein the compound is an anti-NaPi-IIb antibody.

[0096] [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 a ribozyme, an antisense molecule, an inhibitor oligonucleotide, an aptamer, a microRNA, and a small interfering RNA (siRNA).

[0097] [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).

[0098] [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): (i) a low-molecular-weight compound having a molecular weight of 2000 g / mol or less, (ii) an anti-NaPi-IIb antibody, and (iii) a polynucleotide selected from the group consisting of an antisense molecule, a microRNA, and a small interfering RNA (siRNA).

[0099] [D-19] The compound according to any one of [D-1] to [D-18], wherein the compound is administered parenterally. [D-20] The compound according to any one of [D-1] to [D-11] and [D-18], wherein the compound is administered orally.

[0100] [D-21] The compound according to any one of [D-1] to [D-20], which is a compound that selectively inhibits NaPi-IIb among the phosphate transporters.

[0101] [D-22] The compound is a compound that selectively inhibits NaPi-IIb among the phosphate transporters, and the concentration at which phosphate uptake in cells expressing NaPi-IIb or Pit1 is inhibited by 50% (IC ５０ ) ratio (IC ５０ [Pit 1] / IC ５０ The compound according to any one of [D-1] to [D-21], wherein [NaPi-IIb]) is 10 or more.

[0102] [D-23] The compound selectively inhibits NaPi-IIb among the phosphate transporters, and ５０ The ratio of IC ５０ [Pit 2] / IC ５０ The compound according to any one of [D-1] to [D-22], wherein [NaPi-IIb]) is 10 or more.

[0103] [D-24] The concentration of the compound that inhibits phosphate uptake by 50% in cells expressing a phosphate transporter (IC ５０ The compound according to any one of [D-1] to [D-23], wherein the β-glucan group is 10 μg / mol or less.

[0104] [D-25] IC of the inhibitory activity of the compound against human NaPi-IIb ５０ The compound according to any one of [D-1] to [D-24], wherein the β-glucan group is 5 μg / mol or less.

[0105] [D-26] IC of the inhibitory activity of the compound against human NaPi-IIb ５０ The compound according to any one of [D-1] to [D-25], wherein the .alpha.-to-.alpha.-to-.alpha.-to-.alpha.-to-.alpha.-to-.alpha.

[0106] [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 the above formulas 1 to 11, or a salt thereof, or a solvate thereof.

[0107] [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 the above formulas 1 to 4, or a salt thereof, or a solvate thereof.

[0108] [D-29] The compound according to any one of [D-1] to [D-28], wherein the cystic disease is a disease in a mammal. [D-30] The compound according to [D-29], wherein the mammal is a human.

[0109] [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, cystic lung disease, and pancreatic cysts. [D-32] The compound according to any one of [D-2] to [D-30], wherein the cystic disease is accompanied by the formation or expansion of cysts in the kidney, liver, lung, or pancreas.

[0110] [D-33] The compound according to any one of [D-1] to [D-32] for inhibiting a phosphate transporter expressed in the kidney, liver, lung, or pancreas. [D-34] The compound according to any one of [D-1] to [D-33] for use in the treatment or prevention of cystic kidney disease.

[0111] [D-35] The compound according to any one of [D-1] to [D-34] for use in treating or preventing polycystic kidney disease. [D-36] The compound according to [D-35], wherein the polycystic kidney disease is autosomal dominant polycystic kidney disease. [D-37] The compound according to any one of [D-1] to [D-36], for use in suppressing the formation or expansion of renal cysts.

[0112] [E-1] A method for predicting the effectiveness of drug treatment in a patient with a cystic disease, comprising: confirming expression of NaPi-IIb in cells collected from an organ of the patient in which cysts have formed; and determining that a patient in whom the expression has been confirmed is a patient who will benefit from the treatment, wherein the drug is an inhibitor of NaPi-IIb.

[0113] [E-2] The method according to [E-1], wherein the cystic disease is cystic kidney disease. [E-3] The method according to [E-1] or [E-2], wherein the cystic disease is polycystic kidney disease.

[0114] [E-4] The method according to [E-3], wherein the polycystic kidney disease is autosomal dominant polycystic kidney disease. [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.

[0115] [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. [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.

[0116] [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. [E-9] The method according to any one of [E-1] to [E-5], wherein the inhibitor is an anti-phosphate transporter antibody.

[0117] [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 an anti-NaPi-IIa antibody, an anti-NaPi-IIb antibody, and an anti-NaPi-IIc antibody. [E-11] The method according to any one of [E-1] to [E-5], wherein the inhibitor is an anti-NaPi-IIb antibody.

[0118] [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).

[0119] [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).

[0120] [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): (i) a small molecule compound having a molecular weight of 2000 g / mol or less, (ii) an anti-NaPi-IIb antibody, and (iii) a polynucleotide selected from the group consisting of an antisense molecule, a microRNA, and a small interfering RNA (siRNA).

[0121] [E-15] The method according to any one of [E-1] to [E-14], wherein the inhibitor is administered parenterally. [E-16] The method according to any one of [E-1] to [E-7] and [E-14], wherein the inhibitor is administered orally.

[0122] [E-17] The method according to any one of [E-1] to [E-16], wherein the inhibitor is a compound that selectively inhibits NaPi-IIb among the phosphate transporters.

[0123] [E-18] The compound is a compound that selectively inhibits NaPi-IIb among the phosphate transporters, and the concentration at which phosphate uptake in cells expressing NaPi-IIb or Pit1 is inhibited by 50% (IC ５０ ) ratio (IC ５０ [Pit 1] / IC ５０ [NaPi-IIb]) is 10 or more.

[0124] [E-19] The compound is a compound that selectively inhibits NaPi-IIb among the phosphate transporters, and the concentration at which phosphate uptake in cells expressing NaPi-IIb or Pit2 is inhibited by 50% (IC ５０ ) ratio (IC ５０ [Pit 2] / IC ５０ [NaPi-IIb]) is 10 or more.

[0125] [E-20] The concentration of the compound that inhibits phosphate uptake by 50% in cells expressing a phosphate transporter (IC ５０ The method according to any one of [E-1] to [E-19], wherein the value of the total amount of the hydroxybenzoates is 10 μg / mol or less.

[0126] [E-21] The concentration of the compound that inhibits phosphate uptake by 50% in cells expressing NaPi-IIb (IC ５０ The method according to any one of [E-1] to [E-20], wherein the value of the total number of nucleotides in ...

[0127] [E-22] The concentration of the compound that inhibits phosphate uptake by 50% in cells expressing human NaPi-IIb (IC ５０ The method according to any one of [E-1] to [E-21], wherein the value of the α-to-β-glucan compound is 1 μg / mol or less.

[0128] [E-23] The method according to any one of [E-1] to [E-19], wherein the inhibitor is selected from the group consisting of compounds represented by formulas 1 to 11 above.

[0129] [E-24] The method according to any one of [E-1] to [E-19], wherein the inhibitor is selected from the group consisting of compounds represented by formulas 1 to 4 above.

[0130] [E-25] The method according to any one of [E-1] to [E-24], wherein the cystic disease is a disease in a mammal. [E-26] The method according to [E-25], wherein the mammal is a human.

[0131] [E-27] The method according to any one of [E-1] to [E-26], wherein the cystic disease is cystic kidney disease, polycystic liver, cystic lung disease, or pancreatic cyst. [E-28] The method according to any one of [E-2] to [E-26], wherein the cyst is a cyst occurring in the kidney, liver, lung, or pancreas. [E-29] The method according to [E-1] to [E-28], wherein the cell is a kidney cell contained in a biological sample derived from the patient.

[0132] [F-1] A pharmaceutical composition for use in suppressing the development of renal cysts in a subject at risk of autosomal dominant polycystic kidney disease, comprising as an active ingredient a compound that inhibits a phosphate transporter.

[0133] [F-2] The pharmaceutical composition according to [F-1], wherein the subject has a confirmed familial occurrence of autosomal dominant polycystic kidney disease. [F-3] The pharmaceutical composition according to [F-1] or [F-2], wherein one of the subject's parents is a patient with autosomal dominant polycystic kidney disease.

[0134] [F-4] The pharmaceutical composition according to any one of [F-1] to [F-3], wherein the subject has a deficiency in PKD1 or PKD2. [F-5] The pharmaceutical composition according to any one of [F-1] to [F-4], wherein the subject has a deficiency in PKD1.

[0135] [F-6] The pharmaceutical composition according to any one of [F-1] to [F-5], wherein the subject is 30 years of age or older. [F-7] The pharmaceutical composition according to any one of [F-1] to [F-6], wherein the subject has three or more cysts confirmed in each of both kidneys by CT, MRI, or ultrasound tomography.

[0136] [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.

[0137] [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. [F-10] The pharmaceutical composition according to any one of [F-1] to [F-9], wherein the phosphate transporter is NaPi-IIb.

[0138] [F-11] The pharmaceutical composition according to any one of [F-1] to [F-10], wherein NaPi-IIb is expressed in kidney cells of a subject. [F-12] The pharmaceutical composition according to any one of [F-1] to [F-11], wherein the compound inhibits a phosphate transporter expressed in the kidney.

[0139] [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, or a polypeptide.

[0140] [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. [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.

[0141] [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. [F-17] The pharmaceutical composition according to any one of [F-1] to [F-13], wherein the compound is an anti-phosphate transporter antibody.

[0142] [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 an anti-NaPi-IIa antibody, an anti-NaPi-IIb antibody, and an anti-NaPi-IIc antibody. [F-19] The pharmaceutical composition according to any one of [F-1] to [F-13], wherein the compound is an anti-NaPi-IIb antibody.

[0143] [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 a ribozyme, an antisense molecule, an inhibitor oligonucleotide, an aptamer, a microRNA, and a small interfering RNA (siRNA).

[0144] [F-21] The pharmaceutical composition according to any one of [F-1] to [F-20], wherein the compound is administered parenterally. [F-22] The pharmaceutical composition according to any one of [F-1] to [F-15], wherein the compound is administered orally.

[0145] [F-23] The pharmaceutical composition according to any one of [F-1] to [F-18], wherein the compound is a compound that selectively inhibits NaPi-IIb among the phosphate transporters.

[0146] [F-24] The compound is a compound that selectively inhibits NaPi-IIb among the phosphate transporters, and the concentration at which phosphate uptake in cells expressing NaPi-IIb or Pit2 is inhibited by 50% (IC ５０ ) ratio (IC ５０ [Pit 2] / IC ５０ The pharmaceutical composition according to any one of [F-1] to [F-23], wherein the saturation index (SAT) of [NaPi-IIb] is 10 or more.

[0147] [F-25] The concentration of the compound that inhibits phosphate uptake by 50% in cells expressing a phosphate transporter (IC ５０ The pharmaceutical composition according to any one of [F-1] to [F-24], wherein the total amount of the hydroxybenzoates is 10 μg / mol or less.

[0148] [F-26] The concentration of the compound that inhibits phosphate uptake by 50% in cells expressing NaPi-IIb (IC ５０ The pharmaceutical composition according to any one of [F-1] to [F-25], wherein the total amount of the hydroxybenzoates is 5 μg / mol or less.

[0149] [E-27] The concentration of the compound that inhibits phosphate uptake by 50% in cells expressing human NaPi-IIb (IC ５０The pharmaceutical composition according to any one of [F-1] to [F-26], wherein the total amount of the hydroxybenzoates is 1 μg / mol or less.

[0150] [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 the above formulas 1 to 11, or a salt thereof, or a solvate thereof.

[0151] [F-29] The pharmaceutical composition according to any one of [F-1] to [F-28], wherein the compound is selected from the group consisting of compounds represented by the above formulas 1 to 4, or a salt thereof, or a solvate thereof.

[0152] [G-1] A method for screening a compound used in the treatment or prevention of a disease selected from cystic kidney disease, polycystic liver disease, cystic lung disease, and pancreatic cysts, which comprises measuring the inhibitory activity of a phosphate transporter.

[0153] [G-2] A method for screening for a compound that suppresses cyst formation or cyst expansion in a mammalian organ, comprising measuring inhibitory activity of a phosphate transporter. [G-3] The method according to [G-2], wherein the organ is the pancreas.

[0154] [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.

[0155] [G-5] The method according to any one of [G-1] to [G-4], wherein the phosphate transporter is NaPi-IIb. [G-6] The method according to any one of [G-1] to [G-5], wherein the disease is a cystic kidney disease.

[0156] [G-7] The method according to [G-6], wherein the cystic kidney disease is polycystic kidney disease. [G-8] The method according to [G-7], wherein the polycystic kidney disease is autosomal dominant polycystic kidney disease.

[0157] [G-9] The method according to any one of [G-1] to [G-8], wherein the disease is a disease in a mammal. [G-10] The method according to [G-9], wherein the mammal is a human. [G-11] The method according to any one of [G-1] to [G-10], wherein the inhibitory activity is a selective inhibitory activity of NaPi-IIb against Pit1 or Pit2.

[0158] In one aspect of the present invention, there are provided pharmaceutical compositions useful for treating or preventing cystic disease, and medicaments for treating or preventing cystic disease. Furthermore, in one aspect of the present invention, there is provided a method for predicting the efficacy of drug treatment in a patient with cystic disease.

[0159] Figure 1a shows HE-stained images of kidney tissue from an ADPKD patient and the expression level of NaPi-IIb. Figure 1b shows HE-stained images of kidney tissue from an ADPKD patient and the expression level of NaPi-IIb. Figure 1c shows HE-stained images of kidney tissue from an ADPKD patient and the expression level of NaPi-IIb. Figure 1d shows HE-stained images of kidney tissue from an ADPKD patient and the expression level of NaPi-IIb. Figure 1e shows HE-stained images of kidney tissue from an ADPKD patient and the expression level of NaPi-IIb. Figure 2a shows HE-stained images of kidney tissue from a B6 mouse and the expression level of NaPi-IIb. (a) shows the results for a B6 mouse, (b) shows the results for a PC1 Conditional KO mouse, and (c) shows the results for a Pcy mouse. Figure 2b shows HE-stained images of kidney tissue from PC1 conditional knockout mice and the expression level of NaPi-IIb. Figure 2c shows HE-stained images of kidney tissue from Pcy mice and the expression level of NaPi-IIb. Figure 3a shows the results of evaluating the effects of tolvaptan and compound 4 on kidney volume in Pcy mice. Figure 3b shows the results of evaluating the effects of tolvaptan and compound 4 on blood urea nitrogen (UN) levels in Pcy mice. Figure 3c shows the results of evaluating the effects of tolvaptan and compound 4 on body weight in Pcy mice. Figure 3d shows the results of evaluating the effects of tolvaptan and compound 4 on urine volume in Pcy mice. Figure 4 shows 3D images of (a) wells containing no stimulating agent or compound 4, (b) wells containing a stimulating agent and no compound 4, and (c) wells containing a stimulating agent and compound 4, among culture wells of kidney tissue from a human ADPKD patient. Figure 5a shows the results of evaluating the effects of tolvaptan and Compound 4 on kidney volume in PC1 conditional knockout mice, Figure 5b shows the results of evaluating the effects of tolvaptan and Compound 4 on body weight in pcy mice, and Figure 5c shows the results of evaluating the effects of tolvaptan and Compound 4 on urine volume in pcy mice.

[0160] Embodiments of the present invention will be described below. However, the present invention is not limited to the following embodiments. The pharmaceuticals for use in treatment or prevention and the methods for treatment or prevention of the present invention may be administered or applied to humans. As used herein, the term "to" indicating a range includes both ends of the range. For example, "A to B" means a range equal to or greater than A and equal to or less than B. As used herein, the term "about," when used in combination with a numerical value, means a range of +10% and -10% of the numerical value. In the present invention, the meaning of the term "and / or" includes any combination of "and" and "or" as appropriate. Specifically, for example, "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.

[0161] In one aspect of the present invention, there is provided a pharmaceutical composition for use in the treatment or prevention of cystic diseases or for inhibiting the formation or expansion of cysts, which comprises as an active ingredient a compound that inhibits a phosphate transporter.

[0162] In one embodiment of the present invention, the "phosphate transporter" is not particularly limited as long as it is involved in phosphorus metabolism in the body. Examples include transporters involved in reabsorption from the kidney, absorption from the digestive tract, transfer between bone and other tissues, and transporters involved in maintaining phosphorus metabolic homeostasis in the body. Examples of phosphate transporters include sodium-dependent phosphate transporters. Sodium-dependent phosphate transporters are sometimes referred to as sodium-phosphate cotransporters, and include type I, type II, and type III phosphate transporters.

[0163] In one embodiment of the present invention, examples of the phosphate transporter include NaPi-IIa, NaPi-IIb, NaPi-IIc, Pit1, and Pit2, with NaPi-IIb being a preferred example.

[0164] In one embodiment of the present invention, the compound that inhibits a phosphate transporter is not particularly limited as long as it has inhibitory activity against a phosphate transporter or inhibits the expression of a phosphate transporter. In this specification, such a compound may also be referred to as a phosphate transporter inhibitor.

[0165] In one embodiment of the present invention, "treatment" means that the pharmaceutical composition of the present invention inhibits the expansion of cysts in an individual's organs, reduces the number of cyst cells, inhibits the proliferation of cyst cells, reduces cyst volume, reduces cyst weight, inhibits the metastasis of cyst cells, or improves various symptoms caused by cysts. In some embodiments, "prevention" in the present invention means inhibiting the formation of cysts, preventing an increase in the number of cyst cells due to the re-proliferation of decreased cyst cells, preventing the re-proliferation of cyst cells whose proliferation has been inhibited, preventing the re-increase in the size of decreased cysts, or preventing the reappearance of cysts that have disappeared (or healed) with the naked eye by local treatment.

[0166] As used herein, the term "pharmaceutical composition" refers to a mixture containing specific ingredients in predetermined amounts or ratios. A pharmaceutical composition may contain a pharmaceutically acceptable carrier in addition to the active ingredient. As used herein, the term "pharmaceutically acceptable carrier" refers to one or more solid or liquid excipient diluents or encapsulating materials suitable for administration to mammals. As used herein, the term "pharmaceutically acceptable" refers to a substance that can be used as a medicine in terms of efficacy, safety, etc.

[0167] Examples of excipients that can be used as pharmaceutically acceptable carriers include sugars such as lactose, glucose, sucrose, etc.; starches such as corn starch and potato starch; cellulose and derivatives such as sodium carboxymethylcellulose, ethylcellulose, methylcellulose, etc.; tragacanth gum 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 oil; polyhydric alcohols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as TWEEN®; wetting agents such as lecithin; colorants; flavors; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline solution; and phosphate buffers.

[0168] 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. The target molecule can be identified by identifying a gene suitable as a drug target, for example, by a method including the following steps: (1) Identifying genes that are disease factors: Genes that are disease factors can be identified by analyzing differentially expressed genes (DEGs) in tissues of normal and pathological groups. (2) Identifying genes suitable as drug targets from the genes identified in (1): Genes suitable as drug targets can be identified from genes that are disease factors by combining multiple gene selection criteria. Gene selection criteria for selecting genes suitable as drug targets include, for example, not being genes related to innate immunity, adaptive immunity, immunocompetent cells, or inflammation; not being genes related to fibrosis associated with chronic inflammation; and being genes related to membrane proteins. It is preferable that all of these gene selection criteria be satisfied.

[0169] In one aspect of the present invention, the expression of NaPi-IIb can be confirmed, for example, according to the method described in Non-Patent Document 10. More specifically, it can be confirmed by the method described below.

[0170] 1) Tissue containing cysts is excised from the organ and embedded in OCT to create a frozen block. 2) The frozen block is sliced, attached to a Visium Gene Expression slide, and HE stained. 3) After obtaining an HE-stained image, cDNA is prepared and next-generation sequencing analysis is performed. 4) Sequence analysis of the short-read sequence library is performed on the cDNA. 5) The results of the sequence analysis are reflected in the HE-stained image. 6) The number of each gene in each spot calculated by sequencing analysis is corrected by the number of housekeeping genes and nucleic acids in each spot to determine the expression level of each gene.

[0171] In one aspect of the present invention, high expression of NaPi-IIb refers to, for example, a case in which NaPi-IIb is expressed in 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 area of ​​the entire organ tissue image in an HE-stained image of organ tissue that reflects the results of sequence analysis obtained by the above-mentioned method.

[0172] In one aspect of the present invention, a disease involving NaPi-IIb refers to a disease in which NaPi-IIb is involved in the onset, aggravation, and / or continuation of a cystic disease. "A cystic disease involved in the formation, aggravation, and / or continuation of a cystic disease" includes not only a cystic disease in which NaPi-IIb is directly involved in the formation, aggravation, and / or continuation of a cystic disease, but also a cystic disease in which NaPi-IIb is indirectly involved. Although not particularly limited, a cystic disease involving NaPi-IIb may refer to, for example, a cystic disease in which an increase in NaPi-IIb is involved in the formation, aggravation, and / or continuation of a cystic disease.

[0173] In one aspect of the present invention, a cyst associated with NaPi-IIb refers to a cyst in which NaPi-IIb is involved in the formation, expansion, progression, and / or continuation of the cyst. "A cyst in which NaPi-IIb is involved in the formation, expansion, progression, and / or continuation of the cyst" includes not only a cyst that is directly involved in the formation, expansion, progression, and / or continuation of the cyst, but also a cyst that is indirectly involved. Although not particularly limited, a cyst associated with NaPi-IIb may refer to, for example, a cyst in which an increase in NaPi-IIb is involved in the formation, expansion, progression, and / or continuation of the cyst.

[0174] In one aspect of the present invention, the compound that inhibits a phosphate transporter is not particularly limited and may be a known compound or a compound identified by the screening described below, but is preferably at least one compound selected from the group consisting of low molecular weight compounds, polypeptides, and polynucleotides.

[0175] The polypeptides include full-length polypeptides encoded by genes, as well as fragments thereof, chemically synthesized polypeptides, cyclic polypeptides, and glycopeptides. The polypeptides also include antibodies and antigen peptides, and the antibodies may be polyclonal or monoclonal. The antibodies include complete antibodies as well as antibody fragments (e.g., Fab, Fab', F(ab')). ２ , Fv, scFv, sc(Fv) ２ The antibody also includes antibodies (e.g., dsFv, diabodies, etc.) and multimers thereof, minibodies to which antibody variable regions are bound, and antibody-drug conjugates (ADCs). The antibody is preferably an 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 even more preferably an anti-NaPi-IIb antibody.

[0176] Examples of the polynucleotide include ribozymes, antisense molecules, inhibitor oligonucleotides, aptamers, microRNAs, and small interfering RNAs (siRNAs), with antisense molecules, microRNAs, and siRNAs being preferred. The polynucleotides include full-length polynucleotides as well as fragments thereof and synthetic polynucleotides. The molecular weight unit used in this disclosure is "g / mol" (hereinafter, the molecular weight unit may be omitted in this specification). According to one embodiment of the present invention, the compound has a molecular weight of 2000 g / mol or less, 1800 g / mol or less, 1600 g / mol or less, 1400 g / mol or less, 1200 g / mol or less, 1000 g / mol or less, 800 g / mol or less, 600 g / mol or less, 400 g / mol or less, or 200 g / mol or less. Specific examples thereof include compounds, salts thereof, or solvates thereof described in WO2012 / 006475, WO2011 / 136269, WO2013 / 062065, WO2013 / 082756, WO2013 / 082751, and WO2013 / 129435. Further specific examples thereof include compounds represented by the following formulas 1 to 11, or pharmaceutically acceptable salts thereof.

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183] When using the pharmaceutical composition of the present invention, its administration method may be oral or parenteral. Parenteral administration methods include rectal, intravenous, intramuscular, subcutaneous, intracisternal, intravaginal, intraperitoneal, intravesical, or topical (infusion, powder, ointment, gel, or cream) administration, and inhalation (oral or nasal spray). Its dosage forms include, for example, tablets, capsules, granules, powders, pills, aqueous and non-aqueous oral solutions and suspensions, and parenteral solutions filled in containers adapted for individual dosages. The dosage forms can also be adapted for various administration methods, including controlled-release formulations such as subcutaneous implants.

[0184] The above-mentioned preparations are produced by well-known methods using additives such as excipients, lubricants (coating agents), binders, disintegrants, stabilizers, flavoring agents, diluents, etc. Examples of excipients include starch such as potato starch and corn starch, lactose, crystalline cellulose, calcium hydrogen phosphate, etc.

[0185] Examples of coating agents include ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, shellac, talc, carnauba wax, and paraffin.

[0186] Examples of binders include polyvinylpyrrolidone, macrogol, and compounds similar to the above-mentioned excipients. Examples of disintegrants include compounds similar to the above-mentioned excipients, as well as chemically modified starches and celluloses such as croscarmellose sodium, carboxymethyl starch sodium, and cross-linked polyvinylpyrrolidone.

[0187] Stabilizers include, for example, parahydroxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.

[0188] Examples of flavoring agents include commonly used sweeteners, acidulants, fragrances, etc. Furthermore, solvents that can be used to produce liquid preparations include ethanol, phenol, chlorocresol, purified water, distilled water, etc.

[0189] Examples of surfactants or emulsifiers include polyoxyl 40 stearate and lauromacrogol.

[0190] In one aspect of the present invention, when a pharmaceutical composition is used, the amount used will vary depending on symptoms, age, body weight, relative health condition, the presence of other medications, the method of administration, etc. For example, a generally effective amount for a patient (warm-blooded animal, particularly a human) is, in terms of the active ingredient (a compound described in this specification used as the active ingredient), preferably 1 to 20 mg per kg of body weight, more preferably 1 to 10 mg per kg of body weight per day in the case of an oral preparation, and the daily amount used is preferably in the range of 60 to 1200 mg for an adult patient of normal weight, although it is not necessarily limited to these values.

[0191] In one aspect of the present invention, the inhibitory activity of a compound that inhibits a phosphate transporter can be confirmed by a known measurement method. Here, the indicator for confirming the inhibitory activity is the concentration that inhibits 50% of phosphate uptake in cells expressing the phosphate transporter (IC ５０ ) and can be measured, for example, by the method described in Non-Patent Document 8. That is, it can be measured by the following method.

[0192] 1) CHO cells were transfected with a human NaPi-IIb expression plasmid, a human PiT1 expression plasmid, or a human PiT2 expression plasmid. 2) The medium was replaced with buffer A (145 mM choline chloride, 3 mM KCl, 1 mM CaCl ２ ,0.5mM MgCl ２ Buffer B (145 mM NaCl, 3 mM KCl, 1 mM CaCl) was added to the test compound at final concentrations of 0.01, 0.03, 0.1, 0.3, 1, 3, 10, and 30 μM.２ ,0.5mM MgCl ２ , 5 mM glucose, 5 mM MES (pH 6.5)), buffer A supplemented with DMSO, or buffer B supplemented with DMSO.

[0193] 3) After a certain period of time ３３ P.O. ４ 4) After washing with ice-cold buffer A, add liquid scintillator. ３３ P.O. ４ The amount of uptake is measured. The inhibition rate is calculated using the following formula: Inhibition rate (%) = (1 - (test compound added buffer B treated wells) ３３ P.O. ４ Uptake - DMSO-added buffer A-treated wells ３３ P.O. ４ (uptake) / (DMSO-added buffer B-treated wells ３３ P.O. ４ Uptake - DMSO-added buffer A-treated wells ３３ P.O. ４ Amount of uptake) × 100

[0194] 5) In cells expressing human NaPi-IIb, human PiT1, and human PiT2 ３３ P.O. ４ The concentration that inhibits uptake by 50% (IC ５０ ) (μM) is calculated from the line connecting the two points on either side of the 50% inhibition rate.

[0195] In one aspect of the present invention, the concentration at which phosphate uptake in cells expressing a phosphate transporter is inhibited by 50% (IC ５０ In one aspect of the present invention, the concentration at which phosphate uptake in cells expressing NaPi-IIb is inhibited by 50% (IC value) is 10 μM or less, 5 μM or less, or 1 μM or less. ５０ The concentration (value) is 10 μM or less, 5 μM or less, or 1 μM or less.

[0196] In one aspect of the present invention, the compound that inhibits a phosphate transporter is a compound that selectively inhibits NaPi-IIb, and may be, for example, a compound that selectively inhibits NaPi-IIb relative to Pit1 or Pit2. Selectively inhibiting NaPi-IIb means, for example, a concentration that inhibits 50% of phosphate uptake in cells expressing Pit1, Pit2, or NaPi-IIb (IC ５０ ) ratio (IC ５０ [Pit 1] / IC ５０ [NaPi-IIb]) and / or (IC ５０ [Pit 2] / IC ５０ [NaPi-IIb]) is 10 or more, 100 or more, or 500 or more.

[0197] In one aspect of the invention, a compound that inhibits a phosphate transporter is ５０ [Pit 1] / IC ５０ [NaPi-IIb] and / or IC ５０ [Pit 2] / IC ５０ [NaPi-IIb] is a compound having 10 or more, 100 or more, or 500 or more.

[0198] In one aspect of the present invention, the compounds used as active ingredients in pharmaceutical compositions can be salts or solvates thereof. The salts of the compounds described herein can be pharmaceutically acceptable salts. Salts of the compounds described herein include acid addition salts or base addition salts. Examples of acid addition salts include hydrochloride, hydrobromide, hydroiodide, phosphate, phosphonate, sulfate, etc.; sulfonate salts such as methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate; and carboxylate salts such as acetate, citrate, malate, tartrate, succinate, salicylate, maleate, fumarate, benzoate, malonate, glycolate, oxalate, glucuronate, adipate, glutarate, ketoglutarate, and hippurate. Examples of base addition salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, ammonium salts such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts, and tetraalkylammonium salts, and amino acid salts such as lysine salts, arginine salts, glycine salts, valine salts, threonine salts, serine salts, proline salts, and alanine salts. These salts are produced by contacting the compound with an acid or base that can be used in the production of pharmaceuticals.

[0199] In one aspect of the present invention, a solvate refers to a compound that forms a single molecular group together with a solvent, and is not particularly limited as long as it is a solvate formed with a solvent that is acceptable for ingestion accompanying pharmaceutical administration. Examples include solvates with a single solvent such as hydrates, alcoholates (ethanol solvates, methanol solvates, 1-propanol solvates, 2-propanol solvates, etc.), and dimethyl sulfoxide, as well as solvates formed with multiple solvents per compound molecule, or solvates formed with multiple types of solvents per compound molecule. When the solvent is water, it is called a hydrate.

[0200] The compounds and salts thereof described herein, which are used as active ingredients in pharmaceutical compositions, can exist in several tautomeric forms, such as keto and enol forms, imine and enamine forms, and mixtures thereof. Tautomers may exist as a mixture of tautomers in solution. In solid form, one tautomer usually predominates. While one tautomer may be described, the present invention encompasses all tautomers of the compounds of the present invention. The compounds, salts thereof, or solvates thereof described herein encompass all stereoisomers thereof (e.g., enantiomers, diastereomers (including cis- and trans-geometric isomers)), racemates of the isomers, and other mixtures thereof. The compounds may have, for example, one or more asymmetric centers, and the present invention encompasses racemic mixtures, diastereomeric mixtures, and enantiomers of such compounds.

[0201] The compounds described herein, which are used as active ingredients in pharmaceutical compositions, may contain unnatural proportions of isotope atoms in one or more atoms constituting such compounds. The present invention also includes compounds in which any atom in a compound is replaced with an atom having the same atomic number (number of protons) but a different mass number (the sum of the number of protons and neutrons), thereby replacing the isotopes with an abundance ratio different from the abundance ratio of the isotopes in nature, i.e., compounds labeled with isotope atoms. Examples of isotope elements contained in the compounds of the present specification include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, each of which is ２ H. ３ H. １３ C. １４ C. １５ N, １７ O. １８ O. ３１ P, ３２ P, ３５ S. １８ F. ３６Cl, etc. Compounds labeled with isotope atoms are useful as therapeutic or preventive agents, research reagents (e.g., assay reagents), and diagnostic agents (e.g., in vivo imaging diagnostic agents). Compounds herein containing radioactive or non-radioactive isotopes in all proportions are encompassed within the scope of the present invention. Compounds labeled with isotope atoms can be produced using reagents and solvents containing the corresponding isotope atoms in the same manner as for producing unlabeled compounds.

[0202] The compounds described herein used as active ingredients of pharmaceutical compositions may be in the form of prodrugs. Here, as used herein, the term "prodrug" refers to a derivative of the compound that, after administration, is converted into the compound described herein or a pharmaceutically acceptable salt thereof used as an active ingredient of the pharmaceutical composition by enzymatic or non-enzymatic degradation under physiological conditions. The prodrug may be inactive when administered to a patient, but is converted into a compound having phosphate transporter inhibitory activity in vivo.

[0203] For example, a prodrug is converted into a desired drug form when a specific pH is reached or by the action of an enzyme. A typical prodrug is a compound that generates a free acid in vivo and has a hydrolyzable ester group. Examples of such a hydrolyzable ester group include, but are not limited to, a group represented by the formula -COORx, where Rx is C １－４ Alkyl, C ２－７ Alkanoyloxymethyl, 1-(C ４－９ alkanoyloxy)ethyl, 1-methyl-1-(C ５－１０ alkanoyloxy)-ethyl, (C ３－６ alkoxy)carbonyloxymethyl, 1-[(C ４－７ alkoxy)carbonyloxy]ethyl, 1-methyl-1-[(C ５－８ alkoxy)carbonyloxy]ethyl, N-[(C ３－９ alkoxy)carbonyl]aminomethyl, 1-(N-[(C ４－１０ alkoxy)carbonyl]amino)ethyl, 3-phthalidyl, 4-crotonolactonyl, γ-butyrolactone-4-yl, [N,N-di(C１－２ 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.

[0204] The subject to which the compounds, salts, or solvates of the present disclosure are administered is an animal, preferably a mammal (e.g., a mouse, rat, rabbit, dog, monkey (e.g., a cynomolgus monkey), or human), and particularly preferably a human. The human may be an adult (18 years of age or older) or a child (under 18 years of age). The child is preferably, for example, 6 months of age or older.

[0205] In one aspect of the present invention, a pharmaceutical composition containing a compound that inhibits a phosphate transporter can be used in the prevention or treatment of cystic diseases or in the inhibition of cyst formation or expansion. Cystic diseases include, for example, cystic kidney disease, polycystic liver, cystic lung disease, and pancreatic cysts. Cyst formation or expansion can occur in, for example, the kidney, liver, lung, or pancreas.

[0206] In one aspect of the present invention, pharmaceutical compositions comprising compounds that inhibit phosphate transporters may be used in the treatment or prevention of cystic kidney diseases, including polycystic kidney disease, autosomal dominant polycystic kidney disease (ADPKD), and the like, or in inhibiting the formation or expansion of renal cysts. In addition to the diseases described above, examples of cystic kidney diseases include multiple simple renal cysts, renal tubular acidosis, multicystic kidney, multicystic dysplastic kidney, multilocular cysts of the kidney, medullary cystic disease of the kidney, juvenile nephronophthisis, acquired cystic disease of the kidney, and autosomal recessive polycystic kidney disease.

[0207] Polycystic kidney disease can be diagnosed, for example, by confirming the presence of multiple cysts in both kidneys in an imaging test (CT, MRI, ultrasound, etc.). In one embodiment of the present invention, polycystic kidney disease is diagnosed when three or more, or five or more cysts are found in each kidney.

[0208] In one aspect of the present invention, the term "effective amount" refers to a dose of a phosphate transporter inhibitor that is effective for treating or preventing a disease (particularly a cystic disease in the present invention) in an individual. Examples of such a dose include, but are not limited to, a single dose of 0.0001 mg to 1000 mg per kg of body weight, preferably 0.001 mg to 100 mg per kg of body weight, and more preferably 0.01 to 50 mg per kg of body weight, administered once every 1 to 10 weeks, preferably once every 1 to 8 weeks, and more preferably once every 1 to 4 weeks.

[0209] In one aspect of the present invention, the following embodiments are provided: (1) A compound that inhibits NaPi-IIb, for use in treating or preventing cystic kidney disease in a mammal, selected from the group consisting of the following (i) to (iii): (i) a small molecule compound having a molecular weight of 2000 g / mol or less, (ii) an anti-NaPi-IIb antibody, and (iii) a polynucleotide selected from the group consisting of an antisense molecule, a microRNA, and a small interfering RNA (siRNA).

[0210] (2) A compound that inhibits NaPi-IIb, for use in suppressing renal cyst development in a mammal, selected from the group consisting of (i) to (iii) below: (i) a small molecule compound having a molecular weight of 2000 g / mol or less, (ii) an anti-NaPi-IIb antibody, and (iii) a polynucleotide selected from the group consisting of an antisense molecule, a microRNA, and a small interfering RNA (siRNA).

[0211] In one aspect of the present invention, there is provided a method for predicting the efficacy of drug treatment in a patient with a cystic disease, comprising confirming expression of NaPi-IIb in cells collected from an organ in which cysts have formed in the patient, wherein the drug is an inhibitor of NaPi-IIb.

[0212] In one aspect of the present invention, there is provided a method for predicting the efficacy of a drug treatment in a patient with cystic kidney disease, comprising confirming the expression of NaPi-IIb in renal cells collected from the patient. Here, the drug is an inhibitor of NaPi-IIb. The renal cells collected from the patient with cystic kidney disease can be, for example, cells obtained by kidney biopsy, specifically, cells obtained by ultrasound-guided needle biopsy or open kidney biopsy.

[0213] In one aspect of the present invention, a pharmaceutical composition for use in suppressing the development of renal cysts is provided, comprising as an active ingredient a compound that inhibits a phosphate transporter. Renal cysts can be diagnosed, for example, by imaging tests (ultrasound, CT, MRI, etc.). In one embodiment of the present invention, the pharmaceutical composition is used in subjects at risk for autosomal dominant polycystic kidney disease up until the onset of cystic kidney disease. In another embodiment of the present invention, the pharmaceutical composition is used to suppress further development of renal cysts, i.e., to suppress the progression of the disease, even after the onset of cystic kidney disease.

[0214] In one aspect of the present invention, a compound that inhibits a phosphate transporter or a composition containing the compound is administered to a subject in whom familial occurrence of autosomal dominant polycystic kidney disease has been confirmed. Here, familial occurrence is confirmed by the presence or absence of affected individuals in parents, siblings, grandfathers, grandmothers, uncles, aunts, cousins, etc. In one aspect of the present invention, a compound that inhibits a phosphate transporter is administered to a subject in which one of the parents has chromosomal dominant polycystic kidney disease.

[0215] In one aspect of the present invention, a compound that inhibits a phosphate transporter or a composition comprising the compound is administered to a subject having a deficiency in PKD1 or PKD2, wherein the deficiency in PKD1 or PKD2 can be confirmed in cells obtained from the subject by methods known to those skilled in the art. In one embodiment of the present invention, the subject has a deficiency in PKD1.

[0216] The age of a subject to which a compound that inhibits a phosphate transporter or a composition containing the compound is administered is not particularly limited, and may be, for example, 15 years or younger, 16 years or older, 20 years or older, 25 years or older, 30 years or older, 35 years or older, 40 years or older, 45 years or older, 50 years or older, 60 years or older, or 70 years or older. In one aspect of the present invention, the compound or composition is administered to a subject 30 years or older.

[0217] The cerebrovascular diseases and cyst formation or enlargement described herein can be diagnosed or confirmed by examination methods known to those skilled in the art, such as CT, MRI, or ultrasound imaging. In one aspect of the present invention, a compound that inhibits a phosphate transporter or a composition containing the compound is administered to a subject in whom one or more cysts have been confirmed in a specific organ, such as the kidney, liver, lung, or pancreas. In one aspect of the present invention, the subject is one in whom one or more cysts have been confirmed in the kidney. Specifically, the compound or composition is administered to a subject in whom three or more cysts have been confirmed in each kidney by CT, MRI, or ultrasound imaging.

[0218] In one aspect of the present invention, there is provided a method for screening for a compound used in the treatment or prevention of a disease selected from cystic disease, polycystic liver disease, cystic lung disease, and pancreatic cysts, which comprises measuring the inhibitory activity of a phosphate transporter. In another aspect of the present invention, there is provided a method for screening for a compound that suppresses cyst formation or cyst expansion in a mammalian organ, which comprises measuring the inhibitory activity of a phosphate transporter. Hereinafter, these screening methods may sometimes be referred to as "compound screening methods."

[0219] Furthermore, a compound that inhibits a phosphate transporter screened by the above-described compound screening method can be used to provide a pharmaceutical composition containing a compound that inhibits a phosphate transporter as an active ingredient, for treating or preventing a disease in which a phosphate transporter is involved, such as cystic disease, polycystic liver disease, cystic lung disease, or pancreatic cysts, or cystic kidney disease.

[0220] The test compound to be used in the screening method for compounds used as active ingredients in pharmaceutical compositions is not particularly limited, and examples include at least one selected from the group consisting of low molecular weight compounds, polypeptides, and polynucleotides listed above as compounds that inhibit phosphate transporters. More specific examples of the test compound include synthetic low molecular weight compound libraries, expression products of gene libraries, peptide libraries, siRNA, antibodies, bacterially released substances, extracts and culture supernatants of cells (microorganisms, plant cells, animal cells), purified or partially purified polypeptides, extracts derived from marine organisms, plants, or animals, and random phage peptide display libraries. The test compound may also be a derivative of a known phosphate transporter.

[0221] The compound screening method may include selecting a compound having inhibitory activity against a phosphate transporter. The inhibitory activity against a phosphate transporter in the compound screening method can be measured by a known method. As described above, the indicator for confirming the inhibitory activity is the concentration at which phosphate uptake in cells expressing the phosphate transporter is inhibited by 50% (IC ５０ ) may be.

[0222] In one aspect of the present invention, the following screening methods are provided: (1) A method for screening for a compound used in the treatment or prevention of cystic kidney disease in a mammal, comprising measuring inhibitory activity against NaPi-IIb and selecting a compound having inhibitory activity against NaPi-IIb. (2) In one aspect of the present invention, a method for screening for a compound that suppresses cyst formation or cyst expansion in a mammalian organ, comprising measuring inhibitory activity against NaPi-IIb and selecting a compound having inhibitory activity against NaPi-IIb. (3) In one aspect of the present invention, a method for screening for a compound that suppresses cyst formation or cyst expansion in a mammalian kidney, comprising measuring inhibitory activity against NaPi-IIb and selecting a compound having inhibitory activity against NaPi-IIb.

[0223] The present invention will now be described in more detail with reference to the following examples, which are not intended to limit the scope of the invention. All starting materials and reagents were obtained from commercial suppliers or synthesized using known methods.

[0224] Pharmacological Test Examples Test Example 1: In cells expressing human NaPi-IIb, human PiT1, or human PiT2 ３３ P.O. ４ Uptake inhibition evaluation

[0225] 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 in a 96-well plate, and the cells were incubated under CO ２ The medium was then incubated in an incubator for 16 hours. The medium was then reconstituted with buffer A (145 mM choline chloride, 3 mM KCl, 1 mM CaCl ２ ,0.5mM MgCl ２ Buffer B (145 mM NaCl, 3 mM KCl, 1 mM CaCl) was added to the test compound so that the final concentrations were 0.01, 0.03, 0.1, 0.3, 1, 3, 10, and 30 μM, respectively. ２ ,0.5mM MgCl ２ , 5 mM glucose, 5 mM MES (pH 6.5)), buffer A supplemented with DMSO, or buffer B supplemented with DMSO. ３３ P.O. ４ (PerkinElmer Japan Co., Ltd.) was added in an amount of 1 / 20, and the reaction was allowed to proceed at room temperature. After washing with ice-cold buffer A, the plate was washed with liquid scintillator (MicroScint ＴＭ -20, product number 6013621, PerkinElmer Japan Co., Ltd.) was added and the mixture was analyzed using a Top Count NXT (PerkinElmer Japan Co., Ltd.). ３３ P.O. ４ The amount of uptake was measured. The inhibition rate was calculated using the following formula. Here, the fixed time was set to 10 minutes. ３３P.O. ４ "Add 1 / 20 volume of Buffer A containing (PerkinElmer Japan Co., Ltd.)" means " ３３ P.O. ４ (PerkinElmer Japan Co., Ltd.) in an amount of 1 / 20 of the volume of the solution filling the medium.

[0226] Inhibition rate (%) = (1 - (test compound added buffer B treated wells) ３３ P.O. ４ Uptake - DMSO-added buffer A-treated wells ３３ P.O. ４ (uptake) / (DMSO-added buffer B-treated wells ３３ P.O. ４ Uptake - DMSO-added buffer A-treated wells ３３ P.O. ４ Amount of uptake) × 100

[0227] In cells expressing human NaPi-IIb, human PiT1, and human PiT2 ３３ P.O. ４ The concentration that inhibits uptake by 50% (IC ５０ The activity (μM) of Compounds 1 and 2 was calculated from the line connecting the two points on either side of the 50% inhibition rate, and the results are shown in Table 1. Note that Compounds 1 and 2 were not measured for human PiT1 and human PiT2, and therefore are indicated as "-" in Table 1.

[0228]

[0229] As a result of the above test, each test compound showed no activity against human NaPi-IIb expressing cells. ３３ P.O. ４ The uptake inhibitory effect was confirmed.

[0230] Test Example 2: Evaluation of NaPi-IIb Expression Levels in Kidney Tissue of Human ADPKD Patients The amount of NaPi-IIb mRNA in kidney tissue of human ADPKD patients was evaluated using Visium Spatial Gene Expression (10x Genomics). Cyst-containing tissue was excised from kidney tissue excised from ADPKD patients and embedded in OCT to prepare frozen blocks. The frozen blocks were thinly sliced, attached to Visium Gene Expression slides, and subjected to HE staining. After obtaining HE-stained images, cDNA was prepared, and a short-read sequence library of the cDNA was subjected to sequence analysis using NovaSeq6000 (Illumina Inc.). The results of the sequence analysis were reflected in the HE-stained images using Loope Browser (10x Genomics). The expression level of each gene was calculated by correcting the number of each gene in each spot calculated by sequence analysis with the number of housekeeping genes and nucleic acids in each spot. Figures 1a to 1f show HE staining images and NaPi-IIb expression levels. In Figure 1, the grayscale bar indicates the NaPi-IIb expression level, with 4.0 being log ２ 2 ４．０ , and 0.0 indicates log ２ 2 ０．０ Shows.

[0231] The results of the above test showed that NaPi-IIb was highly expressed in the kidney tissues of human ADPKD patients.

[0232] Test Example 3: Evaluation of NaPi-IIb expression levels in kidney tissue of a mouse PKD model. The levels of NaPi-IIb mRNA in kidney tissue of PC1 conditional knockout mice (sequentially bred from 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.) were confirmed using Visium spatial gene expression (10x Genomics). Tamoxifen was orally administered at a dose of 3 mg / kg to PC1 conditional knockout mice for three days starting from 21 days after birth, and kidneys were removed 16 weeks after administration. Kidneys were removed from DBA / 2FG-pcy mice and C57BL / 6J mice at 9 weeks of age. Subsequent procedures were performed in the same manner as in Test Example 2. Figures 2a to 2c show HE staining images and NaPi-IIb expression levels in kidney tissues of PC1 conditional knockout mice, pcy mice, and C57BL / 6J mice. In Figures 2a to 2c, the grayscale bars indicate the NaPi-IIb expression levels, with 4.0 being log ２ 2 ４．０ , and 0.0 indicates log ２ 2 ０．０ Shows.

[0233] The results of the above test showed that NaPi-IIb was highly expressed in the kidney tissue of the mouse PKD model.

[0234] Test Example 4: Evaluation of the effect of suppressing kidney volume increase and renal function decline in pcy mice Using pcy mice, a spontaneous PKD model, 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 were evaluated.

[0235] Pcy mice (5 weeks old at the start of the study) were divided into three groups of 13 mice each. Compound 4 or tolvaptan was administered to the test compound group. The administration period was 5 weeks, with Compound 4 administered subcutaneously once daily and tolvaptan administered subcutaneously once weekly. Compound 4 was administered at 33-40 mg / kg per administration, and tolvaptan was administered at 25-30 mg / kg per administration. Compound 4 and tolvaptan were dissolved in 50% DMSO / 50% glycerol and administered. A group of mice of the parent strain served as a normal control (N=7). The normal control group and the vehicle group of pcy mice were administered 50% DMSO / 50% glycerol at 1 mL / kg.

[0236] Five weeks after the start of administration of the test compound, the left kidney volume (renal volume (mL)) of the mice was calculated by ultrasound examination using the following formula, and the results are shown in Figure 3a. Kidney volume (mL) = π × major axis (mm) × minor axis (mm) × minor axis (mm) × 1000 / 6

[0237] Subsequently, blood was collected from the abdominal vena cava to collect plasma, and the animals were euthanized. Blood urea nitrogen (UN) concentrations (Plasma UN (mg / L)) were measured using an L-type Wako UN (Fujifilm Wako Pure Chemical Corporation) and shown in Figure 3b. Furthermore, the body weights (g) of the mice were measured every 7 days after the start of test compound administration and shown in Figure 3c. Furthermore, 5 weeks after the start of test compound administration, the urine volume (Urine volume (mL / day)) was calculated from the urine specific gravity and weight and shown in Figure 3d.

[0238] As a result of the above test, it was confirmed that Compound 4 has the same inhibitory effect on kidney volume increase and decline in renal function as tolvaptan. Furthermore, it was shown that Compound 4 caused less weight loss and no increase in urine volume compared to tolvaptan.

[0239] Test Example 5: Evaluation of the inhibitory effect of 3D cyst formation using primary cells derived from kidney tissue of a human ADPKD patient Primary cells were isolated from kidney tissue of a human ADPKD patient. In a 2D environment, the isolated cells were cultured for 2 days using DMEM / F-12 (Thermo Fisher Scientific Co., Ltd.) supplemented with 10% FBS. Subsequently, 3D culture was performed for 7 days using 3D Ready Atelocollagen (Koken Co., Ltd.). During 3D culture, 50 μM forskolin (Sigma-Aldrich Co. LLC) and ITS liquid medium supplement (Sigma-Aldrich Co. LLC) were added as stimulating agents to some of the wells to form cysts, and a test compound was added to a final concentration of 30 μM. Additionally, a test compound was added to another well to a final concentration of 30 μM. After 7 days of 3D culture, the cells were fixed using 4% paraformaldehyde (Thermo Fisher Scientific Co., Ltd.), and nucleic acid staining and cell membrane staining were performed using Hoechst 33342 (Thermo Fisher Scientific Co., Ltd.) and CellLight Plasma Membrane-RFP, BacMam 2.0 (Thermo Fisher Scientific Co., Ltd.). 3D imaging and volume analysis were performed using Operetta CLS and image analysis software Harmony (PerkinElmer Japan Co., Ltd.). The inhibition rate was calculated using the following formula.

[0240] Inhibition rate (%)=(1−(volume of wells with stimulating agent and test compound added−volume of wells without stimulating agent and test compound added) / (volume of wells with stimulating agent and without test compound added−volume of wells without stimulating agent and test compound added))×100

[0241] Figure 4 shows three-dimensional images of (a) wells to which no stimulating agent or compound 4 was added, (b) wells to which no stimulating agent or compound 4 was added, and (c) wells to which a stimulating agent or compound 4 was added. Table 2 shows the average inhibition rate (N=3) for each test compound.

[0242]

[0243] As a result of the above test, each test compound was confirmed to have a high inhibitory effect on cyst formation.

[0244] Test Example 6: Evaluation of the effects of suppressing kidney volume increase and renal function decline in PC1 conditional knockout mice Using PC1 conditional knockout mice, a PKD model, 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 were evaluated.

[0245] PC1 conditional knockout mice were orally administered tamoxifen at a dose of 3 mg / kg for three days starting on day 21 of age. PC1 conditional knockout mice (5 weeks old at the start of the study) were divided into three groups of 15 mice each. Compound 4 or tolvaptan was administered as a single agent to the test compound group. The administration period was 16 weeks, with the mice administered subcutaneously once daily. Compound 4 was administered at 33-40 mg / kg per administration, and tolvaptan was administered at 25-30 mg / kg per administration. Compound 4 and tolvaptan were dissolved in 50% DMSO / 50% glycerol and administered. A group of mice not administered tamoxifen served as a normal control (N=7). To the normal control group and the vehicle group of PC1 conditional knockout mice, 50% DMSO / 50% glycerol was administered at 1 mL / kg.

[0246] Sixteen weeks after the start of administration of the test compound, the left kidney volume (renal volume (mL)) of the mice was calculated by ultrasound examination using the following formula, and the results are shown in Figure 5a. Kidney volume (mL) = π × major axis (mm) × minor axis (mm) × minor axis (mm) × 1000 / 6

[0247] The mice were then euthanized. The body weights (g) of the mice were measured every 7 days after the start of administration of the test compound, and the results are shown in Figure 5b. Furthermore, 16 weeks after the start of administration of the test compound, the urine volume (mL / day) was calculated from the specific gravity and weight of the urine, and the results are shown in Figure 5c.

[0248] As a result of the above test, it was confirmed that Compound 4 has an inhibitory effect on the increase and decrease of kidney volume. Furthermore, it was shown that Compound 4 caused less weight loss and no increase in urine volume compared to tolvaptan.

Claims

1. A pharmaceutical composition for use in the treatment or prevention of cystic diseases, containing a compound that inhibits phosphate transporters as an active ingredient.

2. A pharmaceutical composition for inhibiting the formation or enlargement of cysts, comprising a compound that inhibits phosphate transporters as an active ingredient.

3. The pharmaceutical composition according to claim 1 or 2, 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 claim 1 or 2, wherein the phosphate transporter is NaPi-IIb.

5. The pharmaceutical composition according to claim 1, wherein the cystic disease is a disease involving NaPi-IIb.

6. The pharmaceutical composition according to claim 2, wherein the cyst is a cyst involving NaPi-IIb.

7. The pharmaceutical composition according to claim 1 or 2, wherein the compound is at least one selected from the group consisting of low molecular weight compounds, polypeptides, and polynucleotides.

8. The aforementioned compounds are those of formulas 1 to 11 【Chemistry 1】 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 The pharmaceutical composition according to claim 1 or 2, which is a compound selected from the group consisting of compounds represented by, or a salt thereof, or a solvate thereof.

9. The pharmaceutical composition according to claim 1 or 2, 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 claim 2, wherein the cyst is a cyst that forms or enlarges in the kidney, liver, lung, or pancreas.

11. A pharmaceutical composition according to claim 1 or 2 for use in the treatment or prevention of cystic kidney disease.

12. A pharmaceutical composition according to claim 1 or 2 for use in the treatment or prevention of polycystic kidney disease.

13. A method for predicting the effectiveness of drug treatment in patients with cystic diseases, Confirm the expression of NaPi-IIb in cells collected from the organ where the patient's cyst formed. Patients in whom the symptom is confirmed are determined to be patients who will benefit from treatment. The method comprising, wherein the drug is a NaPi-IIb inhibitor.

14. A method for screening compounds for use in the treatment or prevention of a disease selected from cystic kidney disease, polycystic liver disease, cystic lung disease, and pancreatic cysts, comprising measuring inhibitory activity of phosphate transporters.

15. A method for screening compounds that inhibit cyst formation or enlargement in mammalian organs, comprising measuring the inhibitory activity of phosphate transporters.

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