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[Hematopoietic prostaglandin D synthase inhibitors for the treatment of duchenne muscular dystrophy].
- Source :
-
Brain and nerve = Shinkei kenkyu no shinpo [Brain Nerve] 2011 Nov; Vol. 63 (11), pp. 1261-9. - Publication Year :
- 2011
-
Abstract
- Duchenne muscular dystrophy (DMD) is a severe X-linked muscle disease, characterized by progressive skeletal muscle atrophy and weakness. DMD is caused by mutations in the dystrophin gene, which encodes for the cytoskeletal protein dystrophin. DMD is one of the most common types of muscular dystrophies, affecting approximately 1 in 3,500 boys. There is no complete cure for this disease. Clinical trials for gene transfer therapy as a treatment for DMD have been performed but mainly in animal models. Hematopoietic prostaglandin (PG) D synthase (H-PGDS) was found to be induced in grouped necrotic muscle fibers of DMD patients and animal models, mdx mice, and DMD dogs. We found an orally active H-PGDS inhibitor (HQL-79) and determined the 3D structure of the inhibitor-human H-PGDS complex by X-ray crystallography. Oral administration of HQL-79 markedly suppressed prostaglandin D <subscript>2</subscript> (PGD <subscript>2</subscript> ) production, reduced necrotic muscle volume, and improved muscle strength in mdx dystrophic mice. Based on the high-resolution 3D structures of the inhibitor-H-PGDS complex, we designed alternative H-PGDS inhibitors, which were 100- to 3000-times more potent than HQL-79, as assessed by in vitro and in vivo analyses. We used these novel inhibitors for the treatment of DMD dogs and confirmed that oral administration of these inhibitors prevented skeletal muscle atrophy and weakness by decreasing PGD <subscript>2</subscript> production. These results indicate that PGD <subscript>2</subscript> , synthesized by H-PGDS, is involved in the expansion of muscle necrosis in DMD. Thus, inhibition of H-PGDS by using inhibitors is a novel therapy for DMD.
- Subjects :
- Administration, Oral
Animals
Crystallography, X-Ray
Depression, Chemical
Disease Models, Animal
Disease Progression
Dogs
Drug Design
Enzyme Inhibitors chemistry
Enzyme Inhibitors pharmacology
Humans
Intramolecular Oxidoreductases physiology
Lipocalins physiology
Male
Mice
Muscles enzymology
Piperidines chemistry
Piperidines pharmacology
Prostaglandin D2 biosynthesis
Enzyme Inhibitors administration & dosage
Intramolecular Oxidoreductases antagonists & inhibitors
Lipocalins antagonists & inhibitors
Molecular Targeted Therapy
Muscular Dystrophy, Duchenne drug therapy
Muscular Dystrophy, Duchenne enzymology
Piperidines administration & dosage
Subjects
Details
- Language :
- Japanese
- ISSN :
- 1881-6096
- Volume :
- 63
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Brain and nerve = Shinkei kenkyu no shinpo
- Publication Type :
- Academic Journal
- Accession number :
- 22068479