Eastern Virginia Medical School

Gmp Endotherapeutics, Inc.

University of California

Thomas Jefferson University

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

David A Taylor-Fishwick

Aaron I Vinik

Anton Simeonov

David Joseph Maloney

Ajit Jadhav

Diane K Luci

Theodore Holman

Michael Holinstat

Adam Yasgar

Steven McKenzie

Jerry L Nadler

Steven E Mckenzie

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

Methods of preserving and/or protecting pancreatic beta cells by inhibiting NOX-1. In a further aspect, NOX-1 inhibitors are administered to a subject in order to preserve and/or protect beta cells in the prevention or treatment of diabetes. NOX-1 inhibitors are also disclosed.

Methods of preserving and protecting pancreatic beta cells and treating or preventing diabetes by inhibiting NOX-1

Methods to preserve and/or protect beta cell function by contacting a population or preparation of pancreatic cells, beta cells and/or islets with an inhibitor of NADPH oxidase-1 (NOX-1). Methods of treating a subject for diabetes by administering a therapeutically effective amount of a NOX-1 inhibitor to the subject.

An antibody is provided which specifically recognizes and binds to INGAP protein. The antibody is used in competitive binding assays for quantitation of INGAP in biological samples. The assay can be performed on a solid support or in a suspension.

INGAP displacement assays

A an isolated mammalian INGAP 5&#x2033;-regulatory region comprising at least about nucleotides 1-3137 of SEQ ID NO: 2 (SEQ ID NO: 23).

Regulatory sequences for modulation of INGAP expression and reporter constructs

A solid phase assay is used for detecting antibodies to INGAPpeptide, a 15-amino acid peptide that is the biologically active portion of islet neogenesis associated protein (INGAP). The isotype of the antibodies to INGAPpeptide can be determined. A kit can also be used in the detection of anti-INGAPantibodies. Endogenous autoantibodies or antibody production during therapeutic treatment of a mammal with INGAPcan be monitored.

Growing community of inventors

Suffolk, VA, United States of America

David A Taylor-Fishwick