JP-7854711-B2 - Agents that inhibit the progression of chronic kidney disease, and agents that inhibit the progression of proteinuria and/or glomerulosclerosis.

Inventors

• 内海 仁志
• 矢野 雅文
• 小林 茂樹
• 澁谷 正樹
• 名和田 隆司
• 山本 健

Assignees

• 国立大学法人山口大学

Dates

Publication Date

20260507

Application Date

20220614

Claims (5)

1. A chronic kidney disease progression inhibitor containing dantrolene or its pharmaceutically acceptable salts or hydrates as the active ingredient.
2. The chronic kidney disease progression inhibitor according to claim 1, characterized in that the pharmaceutically acceptable salt is a sodium salt.
3. A chronic kidney disease progression inhibitor according to claim 1, characterized in that the patient has chronic kidney disease accompanied by proteinuria and/or glomerulosclerosis.
4. A chronic kidney disease progression inhibitor according to claim 1, for administration to patients who have undergone nephrectomy or who have suffered a renal infarction.
5. An inhibitor of the progression of proteinuria and/or glomerulosclerosis, comprising dantrolene or a pharmaceutically acceptable salt thereof, or a hydrate thereof, as the active ingredient.

Description

Applicable under Article 30, Paragraph 2 of the Patent Law. Published on June 8, 2022 at the following URLs: https://www.amed.go.jp/program/list/15/01/004.html https://www.amed.go.jp/content/000099403.pdf This invention relates to an agent that inhibits the progression of chronic kidney disease, and an agent that inhibits the progression of proteinuria and/or glomerulosclerosis. The number of patients with chronic kidney disease (CKD) continues to increase, with over 330,000 patients undergoing maintenance dialysis. The development of new treatments to slow the progression of CKD is urgently needed. To date, there are no drugs to treat kidney damage. Treatment options have primarily involved meticulous management of blood pressure and blood sugar, as well as the widespread use of renin-angiotensin-aldosterone system inhibitors (ACE inhibitors, angiotensin receptor blockers, mineralocorticoid receptor blockers) to suppress proteinuria. Here, it is disclosed that K201 (also known as JTV519, a Ca2 + leak inhibitor), a 1,4-benzothiazepine derivative, can be used as a therapeutic agent for nephrotic syndrome (NS) or focal segmental glomerulosclerosis (FSGS), both of which are kidney diseases, using a mouse model of NS or FSGS with proteinuria (see Non-Patent Literature 1). This document focuses on the phosphorylation of serine at position 2808 among the many phosphorylation sites possessed by RyR2 in podocytes of the renal glomeruli. It is disclosed that K201 acts on RyR2 together with midbrain astrocellular cell-derived neurotrophic factor (MANF) to inhibit the phosphorylation of serine at position 2808, thereby suppressing Ca2 + leak from the podocyte endoplasmic reticulum (ER) and inhibiting apoptosis of podocytes by inhibiting the above phosphorylation. However, this study was conducted using a proteinuria model mouse, and K201 not only suppresses Ca2 + leakage from RyR, but also suppresses Na + , K + , and Ca2 + channels, raising concerns about potential side effects. Furthermore, RyR2 has numerous phosphorylation sites in addition to the aforementioned serine at position 2808, and the relationship between RyR2 phosphorylation and endoplasmic reticulum stress has not been fully elucidated, requiring further research. Furthermore, it has been disclosed that 1,4-benzothiazepine-1-oxide derivatives improve renal dysfunction by increasing urine volume, sodium excretion, and potassium excretion, and by lowering serum creatinine levels (see Patent Document 1). However, there is no mention of Ca2 + leak. On the other hand, the present inventors have reported that in ryanodine receptors (RyR) on the endoplasmic reticulum (ER) of a wide range of parenchymal organs and tissue cells other than the sarcoplasmic reticulum (SR) of muscle tissue, RyR2 becomes structurally unstable due to external stress such as oxidative stress, causing Ca2 + leakage and leading to ER Ca2 + depletion/cytoplasmic Ca2 + elevation, and that dementia, fatty liver, etc., can occur via ER stress. Conversely, they have reported that various pathological conditions can be improved by pharmacologically (dantrolene as a RyR stabilizer) or genetically (knock-in of a RyR2 internal point mutation: V3599K that increases CaM binding affinity) suppressing the dissociation of calmodulin (CaM) from the domain unzipping during stress (see Non-Patent Literature 2). Furthermore, many molecular chaperones in the ER are Ca2 + -dependent, and it is known that if the Ca2 + concentration in the ER is not properly maintained, the function of the ER will be significantly impaired, leading to ER stress. Incidentally, dantrolene is a compound belonging to the hydantoin derivatives and is known to bind to ryanodine receptors and inhibit the release of Ca2 + from the sarcoplasmic reticulum. In addition to being widely used as a muscle relaxant, dantrolene is also known to have an inhibitory effect on hepatic fibrosis as shown in Patent Document 2, an inhibitory effect on Ras activity or an inhibitory effect on the proliferation of cancer cells as shown in Patent Document 3, and an effect on spasms after nerve damage as shown in Patent Document 4. International Publication No. 2019/117116 brochureJapanese Patent Publication No. 2020-7237International Publication No. 2015/182625 brochureJapanese Patent Publication No. 2016-539167 Park, S.J. et al., “Discovery of endoplasmic reticulum calcium stabilizers to rescue ER-stressed podocytes in nephrotic syndrome”, Proc.Natl.Acad.Sci.USA,vol.116,14154-14163,2019Nakamura Yoshihide et al., “Ryanodine receptor–bound calmodulin is essential to protect against catecholaminergic polymorphic ventricular tachycardia”, JCI Insight. 2019 Jun 6; 4(11): e126112. In Example 2, the glomerular filtration rate (GFR) of each mouse was examined after 12 weeks of rearing post-surgery.In Example 3, the degree of glomerular sclerosis in each mouse after 12 weeks of rearing following surgery was examined.In Example 5, creatinine clearance (CCr)