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1. (WO2018129556) COMPOUNDS AND METHODS FOR INHIBITING NHE-MEDIATED ANTIPORT IN THE TREATMENT OF DISORDERS ASSOCIATED WITH FLUID RETENTION OR SALT OVERLOAD AND GASTROINTESTINAL TRACT DISORDERS

Pub. No.:    WO/2018/129556    International Application No.:    PCT/US2018/013025
Publication Date: Fri Jul 13 01:59:59 CEST 2018 International Filing Date: Wed Jan 10 00:59:59 CET 2018
IPC: C07C 311/29
C07D 401/12
C07D 217/04
C07F 9/38
C07F 9/40
C07F 9/572
C07F 9/62
A61K 31/18
A61K 31/472
A61K 31/4725
A61K 31/517
A61K 31/662
A61K 31/675
A61K 45/06
C07D 215/14
C07D 217/14
C07D 217/16
C07F 9/576
C07F 9/6558
Applicants: ARDELYX, INC.
Inventors: CHARMOT, Dominique
NAVRE, Marc
CARRERAS, Christopher
BELL, Noah
LEADBETTER, Michael R.
JACOBS, Jeffrey W.
DOTSENKO, Irina
DRAGOLI, Dean
HE, Ying
KING, Andrew
LEWIS, Jason
SIEGEL, Matthew
Title: COMPOUNDS AND METHODS FOR INHIBITING NHE-MEDIATED ANTIPORT IN THE TREATMENT OF DISORDERS ASSOCIATED WITH FLUID RETENTION OR SALT OVERLOAD AND GASTROINTESTINAL TRACT DISORDERS
Abstract:
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.