University of California

University of Michigan

Thomas Jefferson University

Eastern Virginia Medical School

The United States of America, as Represented by the Secretary, Department of Health and Human Services

The United States of America as Represented by the Department of Health

Children's Hospital

Galileo Laboratories, Inc.

Theodore Holman

Michael Holinstat

Anton Simeonov

David Joseph Maloney

Ajit Jadhav

Diane K Luci

David A Taylor-Fishwick

Andrew White

Adam Yasgar

Steven McKenzie

Jerry L Nadler

Reheman Adili

David J Maloney

Phillip Crews

Guy Miller

Lesley A Brown

Steve Bobzin

Rakesh Mogul

Klaus Joachin Van Leyen

Ganesha Rai

Jennifer Carroll

Steven E Mckenzie

Disclosed herein are small molecule inhibitors of platelet function, and methods of using the small molecules to treat diseases, such as platelet hemostasis and thrombosis. In particular, disclosed herein are compounds of Formula (I) and pharmaceutically acceptable salts thereof: wherein the substituents are as described.

Inhibitors of platelet function and methods for use of the same

Disclosed herein are small molecule inhibitors of platelet function, and methods of using the small molecules to treat diseases, such as platelet hemostasis and thrombosis. In particular, disclosed herein are compounds of Formula (I) and pharmaceutically acceptable salts thereof: wherein the substituents are as described. 

Human lipoxygenases (LOXs) are a family of iron-containing enzymes involved in catalyzing the oxidation of polyunsaturated fatty acids to provide the corresponding bioactive hydroxyeicosatetraenoic acid (HETE) metabolites. These eicosanoid signaling molecules are involved in a number of physiologic responses such as platelet aggregation, inflammation, and cell proliferation. Platelet-type 12-(S)-LOX (12-LOX) is of particular interest because of its demonstrated role in skin diseases, diabetes, platelet hemostasis, thrombosis, and cancer. Disclosed herein is the identification and medicinal chemistry optimization of a 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide-based scaffold. The compounds display nM potency against 12-LOX and excellent selectivity over related lipoxygenases and cyclooxygenases. In addition to possessing favorable ADME properties, the compounds also inhibit PAR-4 induced aggregation and calcium mobilization in human platelets, and reduce 12-HETE in mouse/human beta cells. The compounds can also be used in methods for treating or preventing a 12-lipoxygenase mediated disease or disorder.

4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase

12(S)-hydroxyeicosatrienoic acid (12(S)-HETrE) compounds and compositions comprising the same are disclosed. Methods of using the compounds in the prevention and treatment of thrombosis and thrombotic disorders are also disclosed.

Hydroxyeicosatrienoic acid compounds and their use as therapeutic agents

A systematic screening has revealed a family of compounds that exhibit inhibitory effects on 12/15-lipoxygenase. Accordingly, the present invention relates to the use of these compounds for the inhibition of 12/15-lipoxygenase and for the treatment of a condition involving 12/15-lipoxygenase. Exemplary conditions include, but are not limited to, stroke, periventricular leukomalacia, cardiac arrest with resuscitation, atherosclerosis, Parkinson's disease, Alzheimer's disease, and breast cancer.

Inhibitors of human 12/15-lipoxygenase

Compounds that are effective lipoxygenase inhibitors, and methods and pharmaceutical compositions for inhibiting lipoxygenases and for treatment of lipoxygenase-mediated conditions in humans and other subjects. The compounds, methods and pharmaceutical compositions utilize subersic terpenoids, jaspic terpenoids, igernellic terpenoids, hippospongic terpenoids, halicondric terpenoids, dictyodendric terpenoids, and/or heteronemic terpenoids, and synthetic derivatives or analogs thereof. Exemplary compounds include (&minus;)-subersic acid, (&plus;)-subersin, jaspaquinol, (&minus;)-jaspic acid, igernellin, halisufate 7, and hipposulfate C and D, and derivatives thereof.

Sponge-derived terpenoids and methods of use

Allosteric inhibitors of lipoxygenase and methods for their use are provided. In many embodiments, the allosteric inhibitors are sulfated long chain alkenyl compounds. The compounds of these embodiments are long chain monounsatured alkenyl compounds having a single sulfate moiety at the 1 position. In many embodiments, the subject compounds range in length from about 14 to 22 carbon atoms and the site of unsaturation is located between the 8 and 14 positions. Specific compounds of interest include 9-oleyl sulfate; 9-palmitoleyl sulfate and 11-eicosenyl sulfate. The subject compounds exhibit lipoxygenase inhibitory activity. As such, the subject compounds find use in treating disease conditions characterized by the presence of undesirable lipoxygenase activity. Also provided are pharmaceutical preparations of the subject compounds.

Allosteric inhibitors of lipoxygenase

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Santa Cruz, CA, United States of America

Theodore Holman