Use of jak inhibitors in kidney disease

Abstract

Provided is the use of a JAK inhibitor in kidney disease. In particular, provided is the use of a JAK inhibitor in the manufacture of a medicament for the treatment or prevention of kidney disease.

Description

[0001] This application claims priority to Chinese patent application 202011458342.X, filed on 2020 / 12 / 11. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This disclosure pertains to the pharmaceutical field and relates to the application of JAK inhibitors in kidney diseases. Background Technology

[0003] In the Kidney Disease Improvement Global Outcomes (KDIGO) guidelines, acute kidney injury (AKI) is defined as a rapid decline in kidney function within 7 days, leading to the accumulation of nitrogenous products in the blood, with or without decreased urine output. The criteria for AKI are: a serum creatinine (Scr) level ≥26.5 μmol / L within 48 hours; or a Scr level ≥1.5 times the baseline value, with a clear or inferred occurrence within the first 7 days; or a urine output <0.5 mL / (kg·h) for 6 hours. Chronic kidney disease (CKD) is defined as kidney damage lasting more than 90 days. AKI and CKD are sometimes related, representing a continuous progression of the same disease. According to the definition in Nat Rev Nephrol. 2017; 13(4):241-257, the transition from AKI to CKD is called acute kidney disease (AKD).

[0004] AKI, AKD, and CKD can be viewed as a continuous process. Initial kidney damage can lead to persistent kidney damage, eventually resulting in CKD. For patients with pre-existing CKD, AKI will worsen their condition, potentially causing AKD on top of CKD and likely leading to further kidney disease progression. (See...) Figure 1 )

[0005] The JAK-STAT pathway transmits signals from extracellular ligands, including many cytokines and chemokines. These responses are most pronounced in lymphoid cells, but are also observed in renal cells such as podocytes, vascular membrane cells, and renal tubular cells. Enhanced expression and activity of JAK1, JAK2, and STAT3 promote diabetic nephropathy, while their inhibition can alleviate the disease. Furthermore, activation of JAK-STAT signaling in autosomal dominant polycystic kidney disease may play an important role in cyst growth (see Curr Opin Nephrol Hypertens. 2015; 24(1):88–95).

[0006] For example, the JAK1 / 2 inhibitor baricitinib has been clinically proven to have some efficacy in treating chronic diabetic nephropathy (NCT01683409), but there are currently no approved JAK inhibitors for the treatment or prevention of kidney disease.

[0007] To date, there has been no evaluation of the role of JAK inhibitors in the prevention or treatment of acute kidney disease (AKD) or acute kidney injury (AKI).

[0008] (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopento[c]pyrrole-2(1H)-carboxamide exhibits superior inhibitory activity against Janus kinase subtype 1 compared to Janus kinase subtype 2 or Janus kinase subtype 3, demonstrating specific selectivity for Janus kinase subtype 1. Compared to pan-JAK inhibitors, it offers better safety and efficacy.

[0009] Summary of the Invention

[0010] This disclosure provides for use in the preparation of medicaments for the treatment or prevention of kidney diseases selected from acute kidney disease (AKD) or acute kidney injury (AKI).

[0011] In some embodiments, the JAK inhibitor is selected from tofacitinib, baricitinib, peficitinib, ruxolitinib, delgocitinib, fedratinib, upadacitinib, filgotinib, pacritinib, abrutinib, etc. brocitinib), PF-06651600, itacitinib, lettaurtinib, PF-06826647, PF-06700841, jactinib, NS-018, BMS-9115443, Gandotinib, INCB-054707, ASN-002, AZD-4205, Cerdulatinib, WXFL10203614, CS12192 or pharmaceutically acceptable salts of the above drugs.

[0012] In other embodiments, the JAK inhibitor has JAK1 activity superior to JAK2 activity and / or JAK3 inhibitory activity, and less than 50%, 40%, 30%, 20%, 10%, or 5% of JAK2 and / or JAK3 activity is inhibited.

[0013] In other embodiments, the JAK inhibitor is selected from (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopento[c]pyrrolo-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof.

[0014] The pharmaceutically acceptable salts described in this disclosure are selected from, but are not limited to, bisulfates, sulfates, mesylates, maleates, tartrates, succinates, acetates, difluoroacetates, fumarates, citrates, citric acid salts, malates, hydrochlorides, sulfates, and phosphates.

[0015] In other embodiments, the JAK inhibitor is selected from (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopento[c]pyrrole-2(1H)-carboxamide hydrogen sulfate.

[0016] Based on serum creatinine (Scr) levels, acute kidney disease (AKD) is classified into stages 0, 1, 2, or 3. AKD stage 0 represents an incomplete recovery state after AKI; AKD stage 0C represents a patient's serum creatinine level exceeding their baseline level but not reaching 1.5 times the baseline level; AKD stage 0B includes serum creatinine levels returning to baseline levels, but still having evidence of kidney damage or decreased kidney reserve; AKD stage 0A includes a state where AKI has occurred, there are no kidney structural or damage markers, but there is a risk of long-term adverse outcomes; patients whose serum creatinine has not returned to baseline levels but have kidney structural or damage markers are classified as AKD stage 0B / C (see Nat Rev Nephrol. 2017; 13(4):241-257). In addition, AKD stage 1 includes serum creatinine levels that are 1.5 to 1.9 times the baseline level; AKD stage 2 includes serum creatinine levels that are 22.9 times the baseline level; AKD stage 3 includes serum creatinine levels that are 3.0 times the baseline level, or serum creatinine levels that exceed 353.6 μmol / L (≥4.0 mg / dL)**, or patients who are currently in need of renal replacement therapy.

[0017] Based on serum creatinine levels, acute kidney injury (AKI) is also classified into four stages: stage 0, stage 1, stage 2, or stage 3. Stage 1 AKI includes a serum creatinine level of 1.5 to 1.9 times the baseline level; stage 2 AKI includes a serum creatinine level of 22.9 times the baseline level; and stage 3 AKI includes a serum creatinine level of 3.0 times the baseline level, or a serum creatinine level exceeding 353.6 μmol / L (≥4.0 mg / dL)**, or a patient requiring renal replacement therapy (see Am J Kidney Dis. Jul; 72(1):136-148).

[0018] In some embodiments, the acute kidney injury (AKI) patient is in stage 3 or lower. In some embodiments, the acute kidney injury (AKI) patient is in stage 2 or lower. In some embodiments, the acute kidney injury (AKI) patient is in stage 1 or lower.

[0019] In some embodiments, the patient with acute kidney disease (AKD) is in stage 3 or lower. In some embodiments, the patient with acute kidney disease (AKD) is in stage 2 or lower. In some embodiments, the patient with acute kidney disease (AKD) is in stage 1 or lower.

[0020] In addition, the kidney diseases described in some implementation schemes are selected from, but not limited to, acute glomerulonephritis, acute interstitial nephritis, idiopathic acute tubulointerstitial nephritis, acute renal failure, kidney injury due to sepsis, drug-induced kidney injury, or surgical kidney injury.

[0021] Drug-induced kidney injury or drug-induced AKI / AKD can occur through mechanisms including: renal insufficiency, toxic and / or ischemic acute tubular necrosis, allergic acute interstitial nephritis, endothelial injury, autoimmune glomerulonephritis, and drug crystal obstruction.

[0022] In optional embodiments of this disclosure, the dosage of the JAK inhibitor administered to human subjects is selected from 0.5-20 mg, including but not limited to 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, ... 8.5mg, 9.0mg, 9.5mg, 10.0mg, 10.5mg, 11.0mg, 11.5mg, 12.0mg, 12.5mg, 13.0mg, 13.5mg, 14.0mg, 14.5mg, 15.0mg, 15.5mg, 16.0mg, 16.5mg, 17.0mg, 17.5mg, 18.0mg, 18.5mg, 19.0mg, 19.5mg or 20.0mg, preferably 1-5mg.

[0023] In some embodiments, the JAK inhibitor is administered to human subjects at a dose of 1 mg. In some embodiments, the JAK inhibitor is administered to human subjects at a dose of 2 mg. In some embodiments, the JAK inhibitor is administered to human subjects at a dose of 4 mg.

[0024] The frequency of administration varies depending on the type and severity of the disease. In an optional embodiment of this disclosure, the JAK inhibitor is administered once, twice, or three times a day.

[0025] In some implementations, the JAK inhibitor is administered to human subjects at a dose of 1 mg once daily.

[0026] In some implementations, the JAK inhibitor is administered to human subjects at a dose of 2 mg once daily.

[0027] In some implementations, the JAK inhibitor is administered to human subjects at a dose of 4 mg once daily.

[0028] In some implementations, the JAK inhibitor is administered to human subjects at a dose of 1 mg twice daily.

[0029] The combined routes of administration described in this disclosure are selected from oral administration, parenteral administration, and transdermal administration, wherein parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, and intramuscular injection.

[0030] In some embodiments, the JAK inhibitors described in this disclosure are administered orally.

[0031] On the other hand, this disclosure also provides a method for treating or preventing kidney disease, comprising administering an effective amount of a JAK inhibitor to a patient with acute kidney disease or acute kidney injury. In some embodiments, the JAK inhibitor is selected from (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopento[c]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof.

[0032] In other embodiments, the JAK inhibitor is selected from (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopento[c]pyrrole-2(1H)-carboxamide hydrogen sulfate.

[0033] This disclosure also provides a JAK inhibitor for the treatment or prevention of kidney diseases selected from acute kidney disease (AKD) or acute kidney injury (AKI). In some embodiments, the JAK inhibitor is selected from (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof. In other embodiments, the JAK inhibitor is selected from (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxamide hydrogen sulfate.

[0034] the term

[0035] The term "effective amount" or "effective therapeutic amount" as used in this disclosure includes an amount sufficient to improve or prevent symptoms or conditions of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxicity. Attached Figure Description

[0036] Figure 1 The continuous progression of AKI, AKD, and CKD following kidney damage.

[0037] Figure 2 : Experimental procedure in Example 1.

[0038] Figure 3 : Experimental procedure in Example 3.

[0039] Figure 4 : Experimental procedure in Example 4.

[0040] Figure 5 : Body weight curve of mice after ischemia-reperfusion model (left) and body weight of mice in each group on the second day after modeling (right).

[0041] Figure 6 Kidney weight (left) and kidney / body weight ratio (right) of mice in each group 48 hours after ischemia-reperfusion modeling.

[0042] Figure 7 Kidney / body weight ratio in mice after administration of compound A at different doses in the ischemia-reperfusion model.

[0043] Figure 8 Blood creatinine (left) and blood urea nitrogen (right) levels in mice in an ischemia-reperfusion model.

[0044] Figure 9 : Dispersion plot of HE pathological scores of the kidneys of mice in the ischemia-reperfusion model (left) and distribution plot of the number of animals with pathological scores (right).

[0045] Figure 10 Blood creatinine (left) and blood urea nitrogen (right) levels in mice in an LPS-induced acute kidney injury model.

[0046] Figure 11 : Blood creatinine (left), blood urea nitrogen (middle), and albumin / creatinine ratio (right) in urine of mice in a cisplatin-induced acute kidney injury model. Detailed Implementation

[0047] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0048] Compound A: (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopento[c]pyrrolo-2(1H)-formamide;

[0049] Compound B: Baricitinib

[0050] Example 1: Ischemia-reperfusion model

[0051] Animals were acclimatized for 7 days after arrival and then randomly divided into groups. Except for the control group, all groups underwent modeling. On day -1, mice in each group received the drug twice daily (BID) via gavage. On the day of surgery (day 0), mice underwent surgery after receiving the drug in the morning. Drug administration continued on day 1, and endpoint treatment was performed on day 2. Blood was collected from mice 24 and 48 hours after surgery. At the endpoint treatment, kidneys were collected and fixed in formalin solution for subsequent HE pathological examination. The specific experimental procedure is as follows: Figure 2 As shown.

[0052] The specific steps of the ischemia-reperfusion surgery are as follows: Mice are anesthetized with 4% chloral hydrate (10 ml / kg, ip). The mice are fixed in a prone position, and an incision is made in their backs. The right kidney is separated, taking care not to damage the adrenal gland and ureter. The renal artery and renal vein are ligated, and the right kidney is removed. The left kidney is then separated, and the renal artery and vein bundles are carefully freed. Miniature arterial clamps are used to clamp the arteries for 30 minutes, then released. The skin is sutured layer by layer, and the mice are placed in a cage to recover.

[0053] Mice were administered the compound via the following regimen, and the body weight, kidney function, blood creatinine and blood urea nitrogen levels, as well as the mortality rate of mice in each group, were observed to evaluate the effects of the compound on the kidneys.

[0054]

[0055]

[0056] Following ischemia-reperfusion modeling, compensatory renal hypertrophy occurred, leading to elevated serum creatinine and blood urea nitrogen levels. Regarding body weight, mice in the 10 mg / kg (mpk) compound A group experienced less weight loss, indicating that compound A had a protective effect against ischemia-reperfusion-induced weight loss, and this effect was stronger than that of the same dose of compound B. Figure 5 Based on the compensatory hypertrophy of the kidneys following ischemia-reperfusion model, the reduction in the kidney / body weight ratio in the treatment group indicates that compounds A and B can improve the compensatory hypertrophy of the kidneys following ischemia-reperfusion model, and compound A has a certain advantage in reducing the kidney / body weight ratio in mice compared to compound B. Figure 6 ).

[0057] Regarding the kidney HE pathology score, a score of 0-3 indicates progressively more severe pathological grading. Compounds A and B significantly improved the kidney HE pathology score in the ischemia-reperfusion mouse model. Figure 9 ).

[0058] Example 2: Ischemia-reperfusion model

[0059] A ischemia-reperfusion model was established according to the method in Example 1. Mice were administered the following drug regimen, and the renal function, serum creatinine, and blood urea nitrogen levels of mice under different dose groups were observed.

[0060]

[0061] Compound A at all dosage groups (2.5 mpk, 5 mpk, and 10 mpk) reduced renal hypertrophy induced by ischemia-reperfusion, and the 5 mpk compound A group showed a significant difference compared to the model group. Figure 7 ).

[0062] In terms of serum creatinine and blood urea nitrogen, compound A (2.5 mpk, 5 mpk, and 10 mpk) at all dosage groups improved the elevation of serum creatinine and blood urea nitrogen caused by ischemia-reperfusion. Compared with the model group, the 5 mpk and 10 mpk compound groups showed significant differences. Furthermore, the renal protective effect of compound A was superior to that of compound B at the same dosage. Figure 8 ).

[0063] In summary, compared with the model group, the mice in the treatment group showed significant improvements in mortality, renal hypertrophy, elevated blood biochemistry, and renal pathology, indicating that compounds A and B exhibited renal protective effects. Furthermore, compound A demonstrated superior renal protective effects compared to compound B.

[0064] Example 3: LPS (lipopolysaccharide)-induced acute kidney disease model

[0065] Animals were acclimatized for 7 days after arrival and then randomly divided into groups. Except for the control group, all groups underwent intraperitoneal injection of LPS to establish the model. From day -2 to day 0, mice in each group were administered the drug by gavage (BID). On the day of model establishment (day 0), animals were intraperitoneally injected with LPS (12 mpk) after administration of the drug in the morning. Blood samples were collected 24 hours later to measure creatinine and blood urea nitrogen. The specific experimental procedure is as follows: Figure 3 As shown.

[0066] Mice were administered the compound via the following regimen, and blood creatinine and blood urea nitrogen levels were observed in each group to evaluate the compound's effect on the kidneys.

[0067]

[0068] Regarding serum creatinine and blood urea nitrogen levels, different doses of compound A significantly reduced LPS-induced increases in serum creatinine and blood urea nitrogen levels, showing significant differences compared to the model group. Compared to the 2.5 mpk compound A group, the 5 mpk and 10 mpk compound A groups exhibited stronger renal protective function. Figure 10 Compound B also showed significant differences compared to the model group.

[0069] Example 4: Cisplatin-induced acute kidney disease model

[0070] Animals were acclimatized for 7 days after arrival and then randomly divided into groups. Except for the control group, all animals underwent intraperitoneal injection of cisplatin to establish the model. From day -3 to day 0, each mouse received the drug twice daily (BID). On the day of model establishment (day 0), after administration of the drug in the morning, animals received an intraperitoneal injection of 15 mg / kg cisplatin solution, continuing administration until day 7. After model establishment, serum and urine samples were collected on days 4 and 7 for the detection of blood creatinine, blood urea nitrogen, and urine albumin / creatinine (UACR). The specific experimental procedure is as follows: Figure 4 As shown.

[0071] Mice were administered the compound via the following regimen, and the levels of blood creatinine and blood urea nitrogen, as well as the mortality rate, were observed in each group to evaluate the effects of the compound on the kidneys.

[0072]

[0073]

[0074] Regarding serum creatinine, blood urea nitrogen, and the urinary albumin / creatinine ratio, compound A dose-dependently reduced cisplatin-induced increases in serum creatinine and urinary protein, with significant differences observed in the 2.5 mpk and 5 mpk administration groups. Compared to compound B, compound A demonstrated stronger renal protective function in the cisplatin model. Figure 11 ).

[0075] Regarding mouse survival, all mice in the cisplatin-induced model group died on the sixth day after modeling (100%, 10 / 10), and different doses of compound A significantly reduced the mortality rate. On the seventh day after modeling, the mortality rate of mice in the compound A-treated group was lower than that in the compound B-treated group at the same dose (40% (4 / 10) vs 80% (8 / 10)).

[0076] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. Use of a JAK inhibitor selected from (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a kidney disease selected from an acute kidney disease (AKD) or an acute kidney injury (AKI).

2. Use according to claim 1, wherein the JAK inhibitor has a JAK 1 inhibitory activity superior to the JAK 2 and / or JAK 3 inhibitory activity and less than 50%, 40%, 30%, 20%, 10% or 5% of the JAK 2 and / or JAK 3 activity is inhibited.

3. Use according to claim 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrogen sulfate, sulfate, mesylate, maleate, tartrate, succinate, acetate, difluoroacetate, fumarate, citrate, malate, hydrochloride and phosphate.

4. Use according to claim 1, wherein the kidney disease is selected from the group consisting of acute glomerulonephritis, acute interstitial nephritis, idiopathic acute tubulointerstitial nephritis, acute renal failure, drug-induced kidney injury or surgical kidney injury.

5. Use according to claim 1, wherein the kidney disease is selected from the group consisting of an acute kidney injury (AKI) patient belonging to stage 3 or less or an acute kidney disease (AKD) patient belonging to stage 3 or less.

6. Use according to claim 1, wherein the JAK inhibitor is administered to a human subject at a dose of 0.5-20 mg.

7. Use according to claim 6, wherein the JAK inhibitor is administered to a human subject at a dose of 1-5 mg.

8. Use according to claim 7, wherein the JAK inhibitor is administered to a human subject at a dose of 1 mg, 2 mg or 4 mg.

9. Use according to claim 1, wherein the JAK inhibitor is administered orally or by intravenous injection.

10. Use according to claim 1, wherein the JAK inhibitor is administered once a day, twice a day or three times a day.

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