University of Virginia Patent Foundation

American Cyanamid Company

Virginia Tech Intellectual Properties, Inc.

Merck + Co., Inc.

Kevin R Lynch

Timothy L MacDonald

Webster L Santos

Michael Oliver Thorner

John R Zysk

Bruce D Gaylinn

Jeffrey K Harrison

Yugesh Kharel

Andrew Kennedy

Thomas P Mathews

Leonardus H T Van Der Ploeg

Andrew D Howard

Steven Brandon Thorpe

Brian R Wamhoff

Brian H Heasley

Michael D Davis

Roy G Smith

Carina P Tan

Qingyun Liu

David L Williams

Margaret A Cascieri

Mark D Okusa

William R Baumbach

Kathleen A Sullivan

Edward A Botchwey, Iii

Jeremy Clemens

Mary J Laughlin

Karen M Carter

Mithun Rajendra Raje

Timothy L Macdonald

Joseph Houck

Christopher E Heise

Theodore N Mellin

Alison Strack

Ruiping Wang

Qingping Jiang

Anusuya Das

Anthony Awojoodu

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

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

Imidamide (amidine) analogs that can inhibit the activity of sphingosine kinase 1 and sphingosine kinase 2 (SphK1 & SphK2) are provided. The compounds can prevent angiogenesis in tumors.

Imidamide 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 application discloses strategies to recruit and mobilize stem cells using S1P receptor selective agonists and antagonists as wells as regulators of chemokine receptors. In an in vivo ischemic model, S1P/S1Pactivation with FTY720 impeded inflammatory cell infiltration and recruited endothelial progenitor cells (EPCs) with the potential to increase microvascular remodeling. S1Pexpression on marrow-derived cells was essential for this remodeling. Concurrent systemic S1Pand CXCR4 antagonism mobilized hematopoietic stem cells (HSCs) with the ability to engraft and repopulate blood cells. Pre-treatment of donor HSCs with FTY720 increased homing toward SDF-1 and improved engraftment in marrow. FTY720-coated bone allografts coupled with systemic administration of VPC01091 enhanced bone allograft integration and new bone formation in bone defects. MSCs pre-treated with FTY720 exhibited increased migration toward SDF-1, a CXCR4+ ligand. The results show that S1P is a very powerful role player in pharmacological marrow-derived stem cell mobilization and recruitment.

Compositions and methods for tissue engineering and cell based therapies

Amidine analogs that can inhibit the activity of sphingosine kinase 1 and sphingosine kinase 2 (SphK1 & SphK2) are provided. The compounds can prevent angiogenesis in tumor cells.

Compositions and methods for inhibiting sphingosine kinase

The present invention provides &#x3b2;-hydroxy phosphonate compounds that are autotaxin inhibitors.

Phosphonate derivatives as autotaxin inhibitors

The present invention provides sphingosine-1-phosphate analogs that are potent, and selective agonists at one or more S1P receptors, specifically the S1Preceptor type, which alter lymphocyte trafficking. The compounds of the invention include compounds having a phosphate moiety as well as compounds with hydrolysis-resistant phosphate surrogates such as phosphonates, alpha-substituted phosphonates, and phosphothionates.

Cycloalkane-containing sphingosine 1-phosphate agonists

The present invention provides LPA analogs that are antagonists at the LPA receptors.

Vinyl phosphonate lysophosphatidic acid receptor antagonists

Compounds that have agonist activity at one or more of the S1P receptors are provided. The compounds are sphingosine analogs that, after phosphorylation, can behave as agonists at S1P receptors.

Bicyclic sphingosine 1-phosphate analogs

Compounds and methods useful for preventing and treating pain, e.g., neuropathic pain, in a subject in need thereof are provided. The compounds can be 'S1P modulating' agents that are capable of inducing a detectable change in S1P receptor activity.

Method for treatment of neuropathic pain

Hydrindane analogs that have agonist activity at one or more of the S1P receptors are provided. The compounds are sphingosine analogs, which, after phosphorylation, can behave as agonists at S1P receptors.

Hydrindane analogs having sphingosine 1-phosphate receptor agonist activity

Sphingosine-1-phosphate analogs that are potent, and selective agonists at one or more S1P receptors, specifically the S1Preceptor type are provided. The disclosed compounds include an optional phosphate moiety as well as compounds with hydrolysis-resistant phosphate surrogates such as phosphonates, alpha-substituted phosphonates, and phosphothionates.

Growing community of inventors

Charlottesville, VA, United States of America

Kevin R Lynch