Gilead Sciences, Inc.

The University of Texas System

Keith Koch

Michael Graupe

Gregory Notte

Britton Kenneth Corkey

Lawrence S Melvin, Jr

Eric N Olson

Nikos C Pagratis

Timothy McKinsey

Johannes Backs

Brooke Harrison

Khai Huynh

The present invention relates to compounds of Formula (I): wherein X, X, X, X, X, X, X, X, R, R, Rare defined above. The compounds have apoptosis signal-regulating kinase ('ASK1') inhibitory activity, and are thus useful in the treatment of ASK1-mediated conditions, including autoimmune disorders, inflammatory diseases, cardiovascular diseases and neurodegenerative diseases. The invention also relates to pharmaceutical compositions comprising one or more of the compounds of Formula (I), and to methods of preparing the compounds of Formula (I).

Apoptosis signal-regulating kinase inhibitors

The present invention relates to compounds of Formula (I): wherein X, X, X, X, X, X, X, X, R, R, Rare as defined above. The compounds have apoptosis signal-regulating kinase ('ASK1') inhibitory activity, and are thus useful in the treatment of ASK1-mediated conditions, including autoimmune disorders, inflammatory diseases, cardiovascular diseases and neurodegenerative diseases. The invention also relates to pharmaceutical compositions comprising one or more of the compounds of Formula (I), and to methods of preparing the compounds of Formula (I).

The present invention relates to compounds of Formula (I): where in X, X, X, X, X, X, X, X, R, R, Rare as defined above. The compounds have apoptosis signal-regulating kinase ('ASK1') inhibitory activity, and are thus useful in the treatment of ASK1-mediated conditions, including autoimmune disorders, inflammatory diseases, cardiovascular diseases and neurodegenerative diseases. The invention also relates to pharmaceutical compositions comprising one or more of the compounds of Formula (I), and to methods of preparing the compounds of Formula (I).

The present invention provides for methods of treating and cardiac hypertrophy, heart failure, dilated cardiomyopathy or hypertension comprising the use of CaMKII-HDAC binding domains. The present invention discloses not only the fact that CaMKII binds to HDAC4 at a specific site, but that HDAC4 may dimerize with other HDACs. Both events can lead to export of HDACs from the nucleus to the cytoplasm, an event associated with the development of heart disease. Thus the methods of treatment and the screening methods of the present invention are novel attempts to prevent, treat or identify therapies for cardiac hypertrophy, heart failure, dilated cardiomyopathy or hypertension.

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Erie, CO, United States of America

Keith Koch