University of California

Thomas Jefferson University

University of Michigan

Eastern Virginia Medical School

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

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

Michael Holinstat

Theodore Holman

Andrew White

Anton Simeonov

David Joseph Maloney

Ajit Jadhav

Diane K Luci

David A Taylor-Fishwick

Adam Yasgar

Steven McKenzie

Jerry L Nadler

Reheman Adili

Paul F Bray

David J Maloney

Leonard Edelstein

Steven E Mckenzie

Theodore R Holman

Andrew D White

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

Disclosed herein are small molecule inhibitors of 12(S)-Lipoxygenase (12-LOX), and methods of using the small molecules to inhibit 12-LOX activation and 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. 

Selective inhibitors of 12(S)-lipoxygenase (12-LOX) and methods for use of the same

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

Disclosed herein are methods for determining whether a PAR4 inhibitor should be administered to a human subject, the methods comprising administering a PAR4 inhibitor to a subject determined to have a 'G' allele for a single-nucleotide polymorphism (SNP) at rs773902, and not administering a PAR4 inhibitor to a subject determined to have an 'A' allele for the SNP at rs773902. A genotyping assay can be used to determine the SNP.

PAR4 inhibitor therapy for patients with PAR4 polymorphism

The present disclosure relates to methods of affecting platelet activation by the use of a PC-TP inhibitor. The PC-TP inhibitor can be administered to a subject in need thereof in order to prevent or treat pathologic thrombosis, or to treat a disorder treatable by a PAR4 inhibitor.

Methods of prevention or treatment for pathologic thrombosis or inflammation

Growing community of inventors

Wallingford, PA, United States of America

Michael Holinstat