Glaxosmithkline LLC

Glaxosmithkline Intellectual Property (no.2) Limited

Karsten Koppetsch

Robert B Perni

Bruce G Szczepankiewicz

Pui Yee Ng

Charles A Blum

Richard Dana Caldwell

Jeremy S Disch

Brian H White

Christopher Oalmann

Ryan Michael Fox

Rebecca L Casaubon

William Henry Miller

Frank Preugschat

The present invention relates to novel substituted bridged urea compounds, corresponding related analogs, pharmaceutical compositions and methods of use thereof. Sirtuin-modulating compounds of the present invention may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders, which include, but are not limited to, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity. The present invention also related to compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.

Substituted bridged urea analogs as sirtuin modulators

Provided herein are stereoisomerically pure ester and carbonate analogues of nicotinamide riboside and nicotinamide riboside hydride, and pharmaceutical compositions and uses thereof. The stereoisomerically pure ester and carbonate analogues of nicotinamide riboside and nicotinamide riboside hydride may be used to treat a disease or disorder that would benefit from increased NAD levels including a mitochondrial disease or disorder, insulin resistance, a metabolic syndrome, diabetes, obesity, for increasing insulin sensitivity in a subject, or to treat or prevent a skin condition. The compounds have general formulas (I) or (II): wherein Ris &#x2014;C(&#x2550;O)&#x2014;X&#x2014;(C-Cstraight chain or branched) alkyl or &#x2014;C(&#x2550;O)&#x2014;X&#x2014;(C-Cstraight chain or branched) alkenyl; each Ris independently selected from hydrogen, and a &#x2014;C(O)&#x2014;X&#x2014;(C-Cstraight chain or branched) alkyl or a &#x2014;C(O)&#x2014;X&#x2014;(C-Cstraight chain or branched) alkenyl; and X is a covalent bond or O.

Nicotinamide riboside analogs and pharmaceutical compositions and uses thereof

Provided herein are crystalline beta-D-nicotinamide riboside chloride compositions and methods of preparation and use thereof. Also provided are related pharmaceutical compositions and methods of use thereof. The crystalline beta-D-nicotinamide riboside chloride compositions may be used to treat a disease or disorder that would benefit from increased NAD levels including a mitochondrial disease or disorder, insulin resistance, a metabolic syndrome, diabetes, obesity, or for increasing insulin sensitivity in a subject.

Preparation and use of crystalline beta-D-nicotinamide riboside

The present invention relates to novel substituted bridged urea compounds of Formula (I): or a pharmaceutically acceptable salt thereof, corresponding related analogs, pharmaceutical compositions and methods of use thereof. Sirtuin-modulating compounds of the present invention may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders, which include, but are not limited to, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity. The present invention also related to compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.

Provided herein are novel substituted bridged urea and related analogs and methods of use thereof. The sirtuin-modulating compounds may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity. Also provided are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent. 

Provided herein is a simple, one-step, non-enzymatic synthesis of O-Acetyl-ADP-ribose (OAADPR) from NAD and sodium acetate in acetic acid. The extension of this reaction to other carboxylic acids, demonstrates that the reaction between NAD, and NAD analogs produces mixtures of the corresponding 2'- and 3&#x2032;-carboxylic esters. Included are O-carboxyl-ADP-ribose compounds and corresponding methods of synthesis (e.g., O-propionyl-ADP-ribose, O-succinyl-ADP-ribose, O-malonyl-ADP-ribose), as well as non-adenosine nucleoside compounds.

Growing community of inventors

Woburn, MA, United States of America

Karsten Koppetsch