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
Document Type and Number:
WIPO Patent Application WO/2010/078449
Kind Code:
A3
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.
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Inventors:
CHARMOT DOMINIQUE (US)
JACOBS JEFFREY W (US)
LEADBETTER MICHAEL ROBERT (US)
NAVRE MARC (US)
CARRERAS CHRIS (US)
BELL NOAH (US)
JACOBS JEFFREY W (US)
LEADBETTER MICHAEL ROBERT (US)
NAVRE MARC (US)
CARRERAS CHRIS (US)
BELL NOAH (US)
Application Number:
PCT/US2009/069852
Publication Date:
September 30, 2010
Filing Date:
December 30, 2009
Export Citation:
Assignee:
ARDELYX INC (US)
CHARMOT DOMINIQUE (US)
JACOBS JEFFREY W (US)
LEADBETTER MICHAEL ROBERT (US)
NAVRE MARC (US)
CARRERAS CHRIS (US)
BELL NOAH (US)
CHARMOT DOMINIQUE (US)
JACOBS JEFFREY W (US)
LEADBETTER MICHAEL ROBERT (US)
NAVRE MARC (US)
CARRERAS CHRIS (US)
BELL NOAH (US)
International Classes:
C07C311/29; A61K31/18; A61K31/472; A61K31/4725; A61K31/517; A61K31/662; A61K31/675; A61K45/06; C07D217/04; C07D401/12; C07F9/38; C07F9/40; C07F9/572; C07F9/62
Domestic Patent References:
| WO2004085404A1 | 2004-10-07 | |||
| WO2006032372A1 | 2006-03-30 | |||
| WO2003048129A1 | 2003-06-12 | |||
| WO2001017954A1 | 2001-03-15 |
Foreign References:
| US20070135383A1 | 2007-06-14 |
Other References:
ERTL P ET AL: "FAST CALCULATION OF MOLECULAR POLAR SURFACE AREA AS A SUM FRAGMENT-BASED CONTRIBUTIONS AND ITS APPLICATION TO THE PREDICTION OF DRUG TRANSPORT PROPERTIES", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, US, vol. 43, no. 20, 1 January 2000 (2000-01-01), pages 3714 - 3717, XP002942715, ISSN: 0022-2623
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