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Publication Number
US-8354396-B2
Publication Date
2013-01-15
Expiration Date
Abstract
The invention relates to methods to identify compounds that can treat autoimmune conditions and treat specified clinical disorders such as multiple sclerosis, ulcerative colitis or arthritis. Compounds include 17α-ethynylandrost-5-ene-3β,11β,7α,17β-tetrol, 4α-acetoxy-17α-ethynylandrost-5-ene-3β,7β,17β-triol, 17α-ethynylandrost-5-ene-3β,4β,7α,17β-tetrol, 17α-ethynylandrost-5-ene-3α,4β,7α,17β-tetrol and 17α-ethynylandrost-5-ene-3α,4β,17β-triol-7-one.
Core Innovation
The invention provides a drug-identification and treatment framework centered on steroidal formula 1 compounds, including 17α-ethynylandrost-5-ene-3β,7β,17β-triol and related esters and analogs. The framework includes selecting test compounds based on modulation of CD4+CD25+ regulatory T cell subsets and, optionally, inhibition of NF-κB transcriptional activity while avoiding significant glucocorticoid receptor, androgen receptor, and estrogen receptor modulation. The disclosed approach links these immune and transcriptional effects to inflammation mediators including NF-κB, IL-6, TNFα, and IκB.
The invention introduces “biodynamic” versus “biostatic” behavior to characterize compounds with transient and partial NF-κB modulation and reduced systemic toxicity. For metabolic disorders, the framework identifies non-PPAR activators with incomplete or partial NF-κB inhibition intended to improve hyperglycemia and insulin sensitivity in vivo. The compound characterization concepts are presented alongside inflammation-mediated mechanisms and described compound structural definitions for the formula 1 steroids.
The invention further describes treatment of inflammation and associated disorders by administering the steroidal compound and maintaining a serum level within a defined range for a defined duration. It specifies oral administration of 17α-ethynylandrost-5-ene-3β,7β,17β-triol to patients in need of inflammation treatment. The disclosed method includes narrowing inflammation indications to particular gastrointestinal and lung inflammation conditions, with lung inflammation conditions selected from a defined list and exemplified by emphysema.
Claims Coverage
The partial claims provided include one independent claim. The independent claim contains key inventive features that are refined by dependent claims adding serum exposure constraints and narrowing the inflammation indications to specified gastrointestinal and lung inflammation conditions, including emphysema.
Oral inflammation treatment with serum-level maintenance
A method to treat inflammation in a patient in need thereof by oral administration of 17α-ethynylandrost-5-ene-3β,7β,17β-triol to maintain a serum level of about 1 ng/mL to about 250 ng/mL for at least about 30 minutes to about 8 hours.
Daily dose ranges for the orally administered compound
The method further includes administering 17α-ethynylandrost-5-ene-3β,7β,17β-triol at about 5 mg/day to about 80 mg/day, and in further refinement at about 5 mg/day to about 40 mg/day.
Inflammatory bowel disease indication
The method specifies that the inflammation is an inflammatory bowel disease.
Defined lung inflammation condition selection
The method specifies that the lung inflammation condition is selected from cystic fibrosis, chronic bronchitis, emphysema, adult respiratory distress syndrome, asthma, or chronic obstructive pulmonary disease.
Emphysema as the lung inflammation condition
The method further specifies that the lung inflammation condition is emphysema.
Across the provided claims, the core claimed approach is oral administration of 17α-ethynylandrost-5-ene-3β,7β,17β-triol with serum-level maintenance, refined by daily dose ranges and by narrowing inflammation treatment to inflammatory bowel disease and selected lung inflammation conditions including emphysema.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treatment of PLP-induced experimental autoimmune encephalomyelitis (EAE) in SJL mice with oral dosing from clinical onset, where multiple steroid compounds show improved clinical course versus vehicle.
Treatment of DNBS-induced inflammatory bowel disease (DNBS colitis) in rats, with reported effects on diarrhea/colonic weight ratio and ulceration.
Additional models related to trauma/ischemia, bone loss/glucocorticoid antagonism, thermal injury, and hemorrhagic shock/trauma protection.
In vitro metabolic stability and CaCo-2 permeability discussion, including tetrol resistance to redox metabolism and limited CaCo-2 permeability while still showing in vivo oral activity for at least one tetrol compound.
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