University of Virginia Patent Foundation

Virginia Tech Intellectual Properties, Inc.

Webster L Santos

Kevin R Lynch

Timothy L MacDonald

Steven Brandon Thorpe

Yumin Dai

Mark D Okusa

Kyle Hoehn

Yugesh Kharel

Andrew Kennedy

Mithun Rajendra Raje

Joseph Houck

Christopher E Heise

Jacob H Murray

Jose A Santiago-Rivera

Elizabeth S Childress

Jacob Murray

Jose Santiago-rivera

Sphingosine kinases are enzymes that catalyze the biosynthesis of sphingosine-1-phosphate. The invention provides prodrugs of compounds that are effective for inhibition of sphingosine kinase type 1, sphingosine kinase type 2, or both, according to formula (I) as described herein. Formula I compounds are useful in the treatment of a range of diseases wherein increasing the level of sphingosine-1-phosphate in blood is medically indicated. The invention also provides pharmaceutical compositions of Formula I compounds.

Sphingosine kinase inhibitor amidoxime prodrugs

This disclosure provides compounds of Formula I, II, and III and pharmaceutically acceptable salts thereof for use as mitochondrial uncouplers, where the variables, e.g. R-R, X, X, and Yare defined in the specification. The disclosure also provides pharmaceutical compositions comprising a compound or pharmaceutically acceptable salt of Formula I, II, or III, alone or in combination with another active compound. Compounds and compositions of Formula I, II, and III are useful for treating or preventing certain conditions such as obesity, type II diabetes, fatty liver disease, insulin resistance, Parkinson's disease, ischemia reperfusion injury, heart failure, non-alcoholic fatty liver disease (NALFD), and non-alcoholic steatohepatitis (NASH). Compounds of Formula I, II, and III are also useful for regulating glucose homeostatis and insulin action.

Compositions and methods for preparing and using mitochondrial uncouplers

The disclosure provides compounds of Formula (I-A) and (I-B) and the pharmaceutically acceptable salts thereof. The variables, R, R, R, X, X, X, Y, Y, and Z are defined herein. Certain compounds of Formula (I-A) and (I-B) act as selective mitochondrial protonophore uncouplers that do not affect plasma membrane potential. These compounds are useful for treating or decreasing the risk of conditions responsive to mitochondrial uncoupling, such as cancer, obesity, type II diabetes, fatty liver disease, insulin resistance, Parkinson's disease, ischemia reperfusion injury, heart failure, non-alcoholic fatty liver disease (NALFD), and non-alcoholic steatohepatitis (NASH), Because mitochondrial uncouplers decrease the production of reactive oxygen species (ROS), which are known to contribute to age-related cell damage, the compounds are useful for increasing lifespan. Compounds and salts of Formulae (I-A) and (I-B) are also useful for regulating glucose homeostasis or insulin action in a patient.

Substituted imidazo[4,5-b]pyridines, imidazo[4,5-b]pyrazines, and oxazolo[4,5- b]pyrazines as mitochondrial uncouplers

Sphingosine kinases are enzymes that catalyze the biosynthesis of sphingosine-1-phosphate. The invention provides prodrugs of compounds that are effective for inhibition of sphingosine kinase type 1, sphingosine kinase type 2, or both, according to formula (I) as described herein. Formula I compounds are useful in the treatment of a range of diseases wherein increasing the level of sphingosine-1-phosphate in blood is medically indicated. The invention also provides pharmaceutical compositions of Formula I compounds. 

Sphingosine kinases are enzymes that catalyze the biosynthesis of sphingosine-1-phosphate. The invention provides compounds that are effective for inhibition of sphingosine kinase type 1, sphingosine kinase type 2, or both. Certain compounds are selective for sphingosine kinase type 2 relative to sphingosine kinase type 1. Compounds of the invention can be used in treatment of a range of diseases wherein increasing the level of sphingosine-1-phosphate in blood is medically indicated. Diseases that can be treated by administration of an effective dose of a compound of the invention include a neoplastic disease that involves excess vascular growth; macular degeneration or diabetic retinopathy; an allergic disease such as asthma, an inflammatory disease of the eye such as uveitis, scleritis, or vitritis; an inflammatory disease of the kidney; a fibrotic disease; atherosclerosis; or pulmonary arterial hypertension. A compound of the invention can be used to improve the integrity of a vascular barrier in a disease where the vascular barrier is disrupted, such as cancer or Alzheimer's disease.

Sphingosine kinase inhibitors

The invention relates to inhibitors of Sphingosine Kinase enzymatic activity, and methods of treating diseases and disorders by administering inhibitors of Sphingosine Kinase enzymatic activity.

Long chain base sphingosine kinase inhibitors

The present invention is directed to compositions comprising lysophosphatidic acid analogs and methods of using such analogs as agonist or antagonists of LPA receptor activity. In addition the invention is directed to LPA receptor agonists that vary in the degree of selectivity at individual LPA receptors (i.e. LPA1, LPA2 and LPA3). More particularly the present invention is directed to LPA analogs wherein the glycerol is replaced with ethanolamine and a variety of substitutions have been linked at the second carbon atom.

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Blacksburg, VA, United States of America

Webster L Santos