Use of new bufadienolide derivatives were synthesized. These steroids have showed to affect cell growth, induce apoptosis and provoke unique changes in intracellular membrane traffic and endosomal pH. Of particular interest are the observations that these compounds are highly effective on leukemia derived cell lines and tumors of the nervous system. Our current work is aimed at the elucidation of the molecular mechanisms involved in these processes and the development of these compounds as a platform for the treatment of cancer.

New indications for synthetic digitalis-like compounds (DLC)

Highlights

• Novel 19-norandrosterone derivatives were proven to be efficacious in the treatment of depressive disorders, in treating digoxin toxicity and to increase cardiac contractility.
• Digitalis-like compounds (DLC) are mammalian steroid hormones involved in the regulation of ion homeostasis and blood pressure. Some of these steroids (e.g. digoxin) are used to treat cardiac insufficiency and some types of arrhythmias. These compounds only cover a small therapeutic window due to their toxicity.
• A group of 19-norandrosterone derivatives were synthesized. Some of these compounds were found to be beneficial in treating depression and others in treating cardiac insufficiency (increase the force of heart contraction, in-vivo) and providing protection from digoxin toxicity.
• Understanding based on molecular studies as well as appropriate experimental animal models.
• Main results: Compound 4 -3 Alpha, 15'dihydroxy-5-Beta -estrane-17Beta-yl furan-2-methyl alcohol decreased immobility in rat Forced Swimming Test of depression; Compound 4 -3' Beta, 15'dihydroxy-5Beta -estrane-17 Beta-yl furan-2-methyl alcohol increased the force of contraction of guinea pig and rabbit heart, in-vivo

Our Innovation

• Novel use of synthetic digitalis-like compounds, such as 19-norandrosterone derivatives, for treatment of depressive disorders, cardiac insufficiency and digoxin toxicity.

Key Features

• Novel treatment for depression associated with new identified mechanisms, unrelated to the monoamine hypothesis of the disease.
• Novel treatment for congestive heart failure based on newly identified mechanisms.
• These steroids do not cause the side effects associated with current treatments

Development Milestones

• Validate the effects in additional animal models of the various diseases
• Toxicity screening in the appropriate animal models
• Synthesis of additional derivatives

The Opportunity

• Depressive disorder is the leading cause of disability in the U.S. for ages 15-44. Major depressive disorder affects approximately 14.8 million American adults, or about 6.7 percent of the U.S. population age 18 and older.
• Congestive heart failure (CHF) is the most common reason for Medicare patients to be admitted to hospital. In the United States, nearly 5 million people have heart failure. Each year about 550,000 new cases are diagnosed. The direct annual cost of CHF in the USA is more than 200 billion dollars.
• The digoxin antidote market is worth an estimated $30 million per annum

project-id 7-2006-395

US patent 7,087,590

US patent 5,874,423