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

US10266488B2 · kind B2 · utility

Assignees

• Eastern Virginia Medical School · US
• The Regents of the University of California Santa Cruz · US
• THE UNITED STATES OF AMERICA, DEPARTMENT OF HEALTH AND HUMAN SERVICES · US
• Thomas Jefferson University · US

Inventors

• David J. Maloney · Point of Rocks, US
• Diane K. Luci · Germantown, US
• Ajit Jadhav · Chantilly, US
• Theodore R. Holman · Santa Cruz, US
• Jerry L. Nadler · Charlottesville, US
• Michael Holinstat · Wallingford, US
• David Taylor-Fishwick · Norfolk, US
• Anton Simeonov · Rockville, US
• Adam YASGAR · Washington, US
• Steven McKenzie · Springfield, US

Key dates

• Filing date: Oct 10, 2014
• Grant date: Apr 23, 2019
• Expiry date: Oct 10, 2034

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C07D417/12
• WIPO field: Organic fine chemistry
• WIPO sector: Chemistry

Abstract

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.