Theravance, Inc.

Ardelyx, Inc.

Advanced Medicine, Inc.

Zeneca Limited

Theravance Biopharma R&d Ip, LLC

Imperial Chemical Industries Limited

Theravance Biopharma Antibiotics Ip, LLC

Michael Robert Leadbetter

Martin Sheringham Linsell

Jeffrey William Jacobs

Noah Bell

Christopher Carreras

Dominique Charmot

Sean Gary Trapp

Jason Gustaf Lewis

Marc Navre

Tao Chen

Paul Ross Fatheree

J Kevin Judice

Daniel D Long

John R Jacobsen

Yan Zhu

Han-Ting Chang

Eric Labonte

Nicholas Reich

Dean R Dragoli

YongQi Mu

Guang Yu Yang

Sabine Axt

Jyanwei Liu

Junning Lee

Bernice M T Lam

Miroslav Rapta

James Bradley Aggen

Edmund J Moran

Timothy J Church

Rakesh K Jain

Pierre-Jean Colson

Priscilla M Van Dyke

Matthew John Siegel

Jeremy Caldwell

Ying Yu

Patricia Finn

Lan Jiang

John H Griffin

Matthew B Nodwell

Gary Luehr

Thomas E Jenkins

Daniel Marquess

Frank X Woolard

Karl J Fisher

Matthew Siegel

Irina Dotsenko

Donald E Schmidt, Jr

Andrew King

John M Gerdes

Qi-Qi Chen

Maureen M McKenna

Richard W Brown

Ying He

Xunxiang Du

Johan Oslob

Chris Carreras

The invention relates to non-systemic TGR5 agonist useful in the treatment of chemotherapy-induced diarrhea, diabetes, Type II diabetes, gestational diabetes, impaired fasting glucose, impaired glucose tolerance, insulin resistance, hyperglycemia, obesity, metabolic syndrome, ulcerative colitis, Crohn's disease, disorders associated with parenteral nutrition especially during short bowel syndrome, and irritable bowel syndrome (IBS), and other TGR5 associated diseases and disorders, having the Formula:

Substituted 4-phenyl pyridine compounds as non-systemic TGR5 agonists

The present disclosure is directed to compounds and methods for the treatment of disorders associated with fluid retention or salt overload, such as heart failure (in particular, congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention. The present disclosure is also directed to compounds and methods for the treatment of hypertension. The present disclosure is also directed to compounds and methods for the treatment of gastrointestinal tract disorders, including the treatment or reduction of pain associated with gastrointestinal tract disorders. The methods generally comprise administering to a mammal in need thereof a pharmaceutically effective amount of a compound, or a pharmaceutical composition comprising such a compound, that is designed to be substantially active in the gastrointestinal (GI) tract to inhibit NHE-mediated antiport of sodium ions and hydrogen ions therein. More particularly, the method comprises administering to a mammal in need thereof a pharmaceutically effective amount of a compound, or a pharmaceutical composition comprising such a compound, that inhibits NHE-3, -2 and/or -8 mediated antiport of sodium and/or hydrogen ions in the GI tract and is designed to be substantially impermeable to the layer of epithelial cells, or more specifically the epithelium of the GI tract. As a result of the compound being substantially impermeable, it is not absorbed and is thus essentially systemically non-bioavailable, so as to limit the exposure of other internal organs (e.g., liver, heart, brain, etc.) thereto. The present disclosure is still further directed to a method wherein a mammal is administered such a compound with a fluid-absorbing polymer, such that the combination acts as described above and further provides the ability to sequester fluid and/or salt present in the GI tract.

Compounds and methods for inhibiting NHE-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders

The present invention provides a compound of formula (I) or a salt thereof: (Formula (I)) wherein X, L, V, R; R, Rand R, are as defined herein. The claimed compounds inhibit the enzyme 11-hydroxysteroid dehydrogenase type 2 (11-HSD2) and as a result are useful in the treatment of hyperkalemia by preventing cortisol from being oxidised to cortisone and thus allowing it to occupy the mineralocorticoid receptor, thus stimulating potassium excretion.

Glycyrrhetinic acid derivatives for use in treating hyperkalemia

The present invention provides a compound of formula (I) or a salt thereof: (I) wherein X, L, V, R, R, Rand R, are as defined herein. These compounds are inhibitors of 11-hydroxysteroid dehydrogenase type 2 (11-HSD-2) and are used to treat hyperkalemia.

Glycyrrhetinic acid derivatives for treating hyperkalemia

The invention relates to non-systemic TGR5 agonist useful in the treatment of chemotherapy-induced diarrhea, diabetes, Type II diabetes, gestational diabetes, impaired fasting glucose, impaired glucose tolerance, insulin resistance, hyperglycemia, obesity, metabolic syndrome, ulcerative colitis, Crohn's disease, disorders associated with parenteral nutrition especially during short bowel syndrome, and irritable bowel syndrome (IBS), and other TGR5 associated diseases and disorders, having the Formula: where R, R, R, R, R, X, X, X, X, Q, and n are described herein.

The present disclosure is directed to compounds and methods for the treatment of disorders associated with fluid retention or salt overload, such as heart failure (in particular, congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention. The present disclosure is also directed to compounds and methods for the treatment of hypertension. The present disclosure is also directed to compounds and methods for the treatment of gastrointestinal tract disorders, including the treatment or reduction of pain associated with gastrointestinal tract disorders.

The present disclosure is directed to compounds of the structure (X):CoreL-NHE)&#x2003;&#x2003;(X)wherein: wherein: wherein:

Compounds and methods for inhibiting NHE-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorder

Compounds having activity as phosphate transport inhibitors, more specifically, inhibitors of intestinal apical membrane Na/phosphate co-transport, are disclosed. The compounds have the following structure (I): including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein X, Y, A, Rand Rare as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

Compounds and methods for inhibiting phosphate transport

Compounds having activity as phosphate transport inhibitors, more specifically, inhibitors of intestinal apical membrane Na/phosphate co-transport, are disclosed. The compounds have the following structure (I): including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein X, Y and A are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

Compounds having activity as phosphate transport inhibitors, more specifically, inhibitors of intestinal apical membrane Na/phosphate co-transport, are disclosed. The compounds have the following structure (I): including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein X, Y, Rand Rare as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

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San Leandro, CA, United States of America

Michael Robert Leadbetter