PDIA4 inhibitors and use thereof for inhibiting β-cell pathogenesis and treating diabetes

{
  "publication_number": "US12605353B2",
  "country": "US",
  "kind": "B2",
  "title": "PDIA4 inhibitors and use thereof for inhibiting β-cell pathogenesis and treating diabetes",
  "abstract": "Disulfide-Isomerase A4 (PDIA4) inhibitors and use thereof for inhibiting pancreatic β-cell pathogenesis and treating diabetes are disclosed. Drug candidates that inhibit PDIA4 with IC50 values ranging from 4 μM to 300 nM are identified. The compounds are highly active in augmenting insulin secretion from pancreatic β-cells. The representative compound No. 8 (4,5-dimethoxy-2-propiolamidobenzoic acid), alone or in combination with metformin, is effective in preserving pancreatic β-cell function, treating and/or reversing, returning blood glucose concentration to a normal level in a diabetic.",
  "claims": [
    "8. A PDIA4 inhibitor-containing pharmaceutical composition, comprising: (i) a PDIA4 inhibitor selected from the group consisting of: and pharmaceutically acceptable salts thereof, and (ii) metformin. 9. The PDIA4 inhibitor-containing pharmaceutical composition of claim 8, wherein the PDIA4 inhibitor is selected from 8 or a pharmaceutically acceptable salt thereof. 10. A method of augmenting insulin secretion from pancreatic β-cells and treating diabetes, comprising: administering to a subject in need thereof a therapeutically effective amount of the PDIA4 inhibitor-containing pharmaceutical composition of claim 2. 11. A method of augmenting insulin secretion from pancreatic β-cells and/or treating diabetes, comprising: administering to a subject in need thereof a therapeutically effective amount of the PDIA4 inhibitor-containing pharmaceutical composition of claim 3. 12. A method of augmenting insulin secretion from pancreatic β-cells, treating diabetes and/or reversing and returning blood glucose concentration to a normal level, comprising: administering to a subject in need thereof a therapeutically effective amount of the PDIA4 inhibitor-containing pharmaceutical composition of claim 5. 13. The method of claim 12, wherein the PDIA4 inhibitor is selected from 8 or a pharmaceutically acceptable salt thereof. 14. The method of claim 10, wherein the PDIA4 inhibitor is selected from 8 or a pharmaceutically acceptable salt thereof. 15. The method of claim 11, wherein the PDIA4 inhibitor is selected from 16. The method of claim 12, wherein the PDIA4 inhibitor is selected from 8 or a pharmaceutically acceptable salt thereof. 17. The method of claim 13, wherein the PDIA4 inhibitor is selected from 8 or a pharmaceutically acceptable salt thereof. 18. A method of inhibiting PDIA4 activity, said method comprising: causing the PDIA4 inhibitor-containing pharmaceutical composition of claim 2 to be in contact with PDIA4 and thereby inhibiting the PDIA4 activity."
  ],
  "description_excerpt": "The present invention relates generally to PDIA4 inhibitors.\n\nType 2 diabetes (T2D) is characterized by peripheral insulin resistance, insufficient insulin secretion and progressive loss of β cell. Decline in β-cell function and mass is a central hallmark of T2D. Accumulating data suggest that preserving functional β-cell mass at early stages can delay and reverse T20. Therefore, identification of the key players in β-cell dysfunction and death could lead to a better understanding of β-cell pathogenesis and T2D development and new strategies for T2D treatment.\n\nProtein disulfide isomerase (PDI) family (21 members) has multiple roles in cellular function and was reported to be implicated in infection, fertilization, coagulation, immunity, tumor metastasis or cell viability/growth. The role of protein disulfide isomerase (PDI) family in health and disease is poorly studied. Protein Disulfide-isomerase A3 (PDIA3) and protein Disulfide-Isomerase A4 (PDIA4) are two members of this family. Their function may not be redundant since mice deficient Pdia3 but not PDIM were shown to be lethal at embryonic stage. So far, no PDI-based drugs have been developed.\n\nApproaches for preserving β-cell function and mass at the early diabetic stage, which can reverse T2D, are highly demanded.\n\nIn one aspect, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,\n\nwherein:\n\nIn one embodiment of the invention, R 6 is H or (C 1 -C 6)alkyl, benzyl, halo(C 1 -C 6)alkyl, - (CH 2) n - Si(CH 3) 3, or carbonyl(C 1 -C 6)alkyne.",
  "cpc": [
    "A61K 31/216",
    "A61K 31/196",
    "A61P 3/10"
  ],
  "ipc": [
    "A61K 31/196",
    "A61K 31/216",
    "A61P 3/10"
  ],
  "assignees": [
    "Academia Sinica"
  ],
  "inventors": [
    "Wen-Chin Yang",
    "Keng-Chang Tsai"
  ],
  "filing_date": "2020-11-15",
  "publication_date": "2026-04-21",
  "grant_date": "2026-04-21",
  "priority_date": "2019-12-02",
  "application_number": "US-202017780482-A",
  "family_id": "76222457",
  "cited_by_count": 0,
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}