Metabasis Therapeutics, Inc.

Sankyo Company, Limited

K Raja Reddy

Mark D Erion

Qun Dang

Serge H Boyer

Srinivas Rao Kasibhatla

M Rami Reddy

Brett C Bookser

Scott J Hecker

Bheemarao G Ugarkar

Edward D Robinson

Venkat Reddy Mali

Zhili Sun

Nicholas Brian Raffaele

Gerard Robert Scarlato

Jeff Stebbins

William Craigo

Michael Matelich

Mali Venkat Reddy

Joseph J Kopcho

Michael C Matelich

David Bernard Smith

Tao Jiang

Robert Huerta Lemus

Haiqing Li

Thanh Huu Nguyen

Matthew P Grote

Jorge E Gomez-Galeno

Paul D Van Poelje

Mingwei Chen

Atul Agurwal

Atul Agarwal

This invention pertains to the use of fused bicycle heterocyclic adducts of thiohydroxy pyridines or pyrimidines as diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitors to treat hyperlipidiemias and various diseases and disorders associated therewith. Other conditions also be ameliorated or avoided, such as high postprandial triglycerides or diet-related hypertriglyceridemia, cardiovascular risk associated with excessive triglycerides, and insulin resistance/glucose intolerance in overweight patients, those with diabetes or other glucose metabolic disorders such as Syndrome X and/or polycystic ovary disease.

Inhibitors of diacylglycerol O-acyltransferase 1 (DGAT-1) and uses thereof

The invention pertains to the use of compounds represented by the formula, Q-G-G-G-G-Z, where Q is  The compounds can be used as diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitors to treat hyperlipidiemias and various diseases and disorders associated therewith. Other conditions also can be ameliorated or avoided, such as high postprandial triglycerides or diet-related hypertriglyceridemia, cardiovascular risk associated with excessive triglycerides, and insulin resistance/glucose intolerance in overweight patients, those with diabetes or other glucose metabolic disorders such as Syndrome X and/or polycystic ovary disease.

The invention pertains to the use of fused bicyclo heterocyclic adducts of thiohydroxy pyridines or pyrimidines as diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitors to treat hyperlipidiemias and various diseases and disorders associated therewith. Other conditions also can be ameliorated or avoided, such as high postprandial triglycerides or diet-related hypertriglyceridemia, cardiovascular risk associated with excessive triglycerides, and insulin resistance/glucose intolerance in overweight patients, those with diabetes or other glucose metabolic disorders such as Syndrome X and/or polycystic ovary disease.

The invention pertains to the use of fused bicyclo heterocyclic adducts of thiohdroxy pridines or primidines as diacylglycerol O-acyltransferase 1 DGAT-1 inhibitors to treat hyperlipidiemias and various diseases and disorders associated therewith. Other conditions also can be ameliorated or avoided, such as high postprandial triglycerides or diet-related hypertriglyceridemia, cardiovascular risk associated with excessive triglycerides, and insulin resistance/glucose intolerance in overweight patients, those with diabetes or other glucose metabolic disorders such as Syndrome X and/or polycystic ovary disease.

The present invention provides for novel compounds of Formula (I) and pharmaceutically acceptable salts and co-crystals thereof which have glucagon receptor antagonist or inverse agonist activity. The present invention further provides for pharmaceutical compositions comprising the same as well as methods of treating, preventing, delaying the time to onset or reducing the risk for the development or progression of a disease or condition for which one or more glucagon receptor antagonist is indicated, including Type I and II diabetes, insulin resistance and hyperglycemia. The present invention also provides for processes of making the compounds of Formula I, including salts and co-crystals thereof, and pharmaceutical compositions comprising the same.

Antagonists of the glucagon receptor

Novel cyclic phosphoramidate prodrugs of drugs of formula I their use in delivery of drugs to the liver, their use in enhancing oral bioavailability, and their method of preparation are described.

Phosphorus-containing prodrugs

Compounds having the formula I or II wherein R, R, B, and V are as defined herein are Hepatitis C virus NS5b polymerase inhibitors. Also disclosed are compositions and methods for treating an HCV infection and inhibiting HCV replication. 

Nucleoside prodrugs and uses thereof

Compounds of Formula I, stereoisomers, and pharmaceutically acceptable salts or prodrugs thereof, their preparation, and their uses for the treatment of hepatitis C viral infection are described: 

2'-C-methyl nucleoside derivatives

Compounds of Formula I, their preparation and synthetic intermediates, and their use in the synthesis of prodrugs: 

Cyclic phosphate diesters of 1,3-propane-1-aryl diols and their use in preparing prodrugs

Novel FBPase inhibitors of the formula I are useful in the treatment of diabetes and other conditions associated with elevated blood glucose.

Aryl fructose-1,6-bisphosphatase inhibitors

Prodrugs of formula I, their uses, their intermediates, and their method of manufacture are described: 

Prodrugs for phosphorus-containing compounds

Novel FBPase inhibitors of the formula I and X are useful in the treatment of diabetes and other conditions associated with elevated blood glucose.

Heteroaromatic inhibitors of fructose 1,6-bisphosphatase

The present invention is directed towards novel cyclic phosph(oramid)ate prodrugs of alcohol-, amine-, and thiol-containing drugs, their preparation, their synthetic intermediates, and their uses. Another aspect of the invention is the use of the prodrugs to treat diseases that benefit from enhanced drug distribution to the liver and like tissues and cells that express cytochrome P450, including hepatitis, cancer, liver fibrosis, malaria, other viral and parasitic infections, and metabolic diseases where the liver is responsible for the overproduction of the biochemical end product, e.g. glucose (diabetes); cholesterol, fatty acids and triglycerides (hyperlipidemia) (atherosclerosis) (obesity). In one aspect, the invention is directed towards the use of the prodrugs to enhance oral drug delivery. In another aspect, the prodrugs are used to prolong pharmacodynamic half-life of the drug. In addition, the prodrug methodology of the current invention is used to achieve sustained delivery of the parent drug. In another aspect, the prodrugs are used to increase the therapeutic index of the drug. In another aspect of the invention, a method of making these prodrugs is described. In another aspect, the prodrugs are also useful in the delivery of diagnostic imaging agents to the liver.

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San Diego, CA, United States of America

K Raja Reddy