2,6-dimethoxy-4-(5-phenyl-4-thiophene-2-yl-1H-imidazol-2-yl)-phenol (DPTIP) a small molecule inhibitor of neutral sphingomyelinase 2 (nSMase-2) for the treatment of neurodegenerative and oncologic diseases
Inventors
SLUSHER, BARBARA • Rojas, Camilo • Thomas, Ajit G. • Haughey, Norman • Ferrer, Marc • Hu, Xin
Assignees
Johns Hopkins University • US Department of Health and Human Services • Office of Technology Transfer
Publication Number
US-11766423-B2
Publication Date
2023-09-26
Expiration Date
2039-03-01
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Abstract
Methods for treating one or more diseases associated with neutral sphingomyelinase 2 (nSMase2) in a subject in need of treatment thereof, the method comprising administering to the subject a therapeutically effective amount of 2,6-dimethoxy-4-(5-phenyl-4-thiophen-2-yl-1H-imidazol-2-yl)-phenol (DPTIP) or a pharmaceutically acceptable salt thereof, are disclosed.
Core Innovation
The invention provides methods for treating diseases associated with neutral sphingomyelinase 2 (nSMase2) by administering a therapeutically effective amount of 2,6-dimethoxy-4-(5-phenyl-4-thiophen-2-yl-1H-imidazol-2-yl)-phenol (DPTIP) or its pharmaceutically acceptable salts. DPTIP is disclosed as a potent, brain-penetrant, non-competitive inhibitor of nSMase2, which inhibits exosome and ceramide biosynthesis in vitro and in vivo.
The problem being addressed is that brains from Alzheimer's disease patients and other neurodegenerative disorders show elevated ceramide, a product of nSMase2 activity, which is implicated in Aβ aggregation and tau propagation via exosome secretion. Existing nSMase2 inhibitors have low potency, poor solubility, and limited brain penetration, limiting their clinical utility.
The disclosed invention overcomes these challenges by discovering DPTIP via high throughput screening as the most potent and drug-like human nSMase2 inhibitor identified to date (IC50=30 nM), with metabolic stability and brain penetration. DPTIP inhibits nSMase2 activity, reduces exosome release from astrocytes, prevents inflammatory biomarker upregulation, and reduces neutrophil infiltration into brain in preclinical models. The invention thus provides a novel therapeutic avenue for neurodegenerative, oncologic, and cardiac diseases associated with nSMase2 dysregulation.
Claims Coverage
The patent contains two independent claims focusing on therapeutic methods and pharmaceutical use of DPTIP to inhibit diseases associated with nSMase2.
Method for treating diseases associated with nSMase2 using DPTIP
Administering a therapeutically effective amount of 2,6-dimethoxy-4-(5-phenyl-4-thiophen-2-yl-1H-imidazol-2-yl)-phenol (DPTIP) or its pharmaceutically acceptable salt to a subject in need to treat one or more diseases associated with neutral sphingomyelinase 2 (nSMase2), specifically in neurodegenerative or oncologic disease contexts.
Selection of neurodegenerative diseases treated by DPTIP
The neurodegenerative diseases treated include Alzheimer's disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and HIV-associated neurocognitive disorders (HAND) as specific examples of diseases associated with nSMase2.
The claims broadly cover therapeutic methods employing DPTIP to inhibit nSMase2 activity and treat neurodegenerative and oncologic diseases, highlighting specific treatment of major neurodegenerative disorders.
Stated Advantages
DPTIP is a potent nSMase2 inhibitor with nanomolar IC50, exhibiting greater potency than previously known inhibitors.
DPTIP has metabolic stability in mouse and human liver microsomes, indicating suitability for in vivo use.
DPTIP exhibits good pharmacokinetic properties including brain penetration suitable for treating CNS diseases.
DPTIP selectively inhibits nSMase2 without affecting related enzymes, supporting specificity.
DPTIP effectively inhibits exosome release in vitro and in vivo, leading to reduced neuroinflammation and immune cell infiltration.
Documented Applications
Treatment of neurodegenerative diseases including Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, and HIV-associated neurocognitive disorders.
Treatment of oncologic diseases.
Treatment of cardiac diseases including myocardial diseases involving hypertrophy, heart failure, and cardiovascular fibrosis-related conditions.
Inhibition of neutral sphingomyelinase 2 activity in cells.
Inhibition of exosome biosynthesis and ceramide biosynthesis in cells.
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