Pdia4 inhibitors and use thereof for inhibiting ß-cell pathogenesis and treating diabetes
AssigneeAcademia Sinica
InventorsWen-Chin YANG, Keng-Chang TSAI
Life of this patent
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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.
Claims20
A compound of formula (I) or a pharmaceutically acceptable salt thereof,
- wherein:
- R1 is —C(═O)OR6;
- R2 is H, (C1-C6)alkyl, benzyl, or —L—R11, wherein L is a bond or (C1-C6)alkylene, and R11 is phenyl, halo, dioxoisoindolin, —NR7R8, or —NR7—CO—R8;
- R3 is H, (C1-C6)alkyl, or benzyl;
- R4 is H, or (C1-C6)alkoxy;
- R5 is (C1-C6)amine, —NR7R8, or —NR7—CO—R8;
- X1 and X2 is each independently —O—, —S—, or a covalent bond;
- R6 is H, halogen, (C1-C6)aryl, benzyl, halo(C1-C6)alkyl, —(CH2)n—Si(CH3)3, or carbonyl(C1-C6)alkyne, wherein n is 1 to 6;
- R7 and R8 is each independently H, (C1-C6)alkoxy, phenyl, benzoyl, halobenzoyl, benzyl, carbonyl(C1-C6)alkyne, (C1-C6)alkyne, oxazole, thiazole, or imidazole;
- wherein optionally the (C1-C6)alkoxy, phenyl, benzoyl and/or benzyl is each independently substituted with one or more substituents selected from F, Cl, Br, I, (C1-C6)alkoxy, (C1-C6)alkyl, or halo(C1-C6)alkyl;
- or R7 and R8 together with the N atom form an benzimidic acid.
The compound or the pharmaceutically acceptable salt thereof of claim or 2, wherein
- R2 is (C1-C6)alkyl, or —L—R11, in which L (C1-C6)alkylene, and R11 is dioxoisoindolin, —NR7R8, or —NR7—CO—R8, in which R7 and R8 is each independently H, phenyl, benzoyl, halobenzoyl, benzyl, carbonyl(C1-C6)alkyne, or oxazole.
Dependencies are inferred from the claim text.