Sanofi-a Ventis Deutschland Gmbh

Sanofi

Sanofi-aventis

Thomas Licher

Hans-Jochen Lang

Klaus Wirth

Uwe Heinelt

Armin Hofmeister

Ursula Schindler

Hans-Willi Jansen

Stefan Schaefer

The present invention relates to methods for determining the in vivo efficiency of a sodium-proton-exchanger (NHE) ion channel ligand comprising the steps of: (a) contacting a cell expressing a sodium-proton-exchanger (NHE) ion channel in vitro with either (i) plasma of an animal and the ion channel ligand or (ii)) the plasma of an animal which has been administered the ion channel ligand; (b) determining the effect of the ion channel ligand on the cell; c) determining ion channel ligand availability by comparing the ligand concentration in the plasma to the concentration of ligand administered; and d) correlating the effect of the ion channel ligand on the cell with the ligand availability to determine the in vivo efficiency of the ligand.

Methods for determining sodium-proton-exchanger ligand efficiency

The invention relates to substituted 4-phenyltetrahydroisoquinolines of formula I wherein R1-R8, N, W, X and Z are defined herein. These compounds and pharmaceutical compositions comprising them are useful in the treatment of respiratory disorders, sleep apnea, kidney disorders, high blood pressure, hypertension, disorders of the central nervous system and the like.

Substituted 4-phenyltetrahydroisoquinolines, pharmaceutical compositions comprising them and therapeutic methods for their use

The present invention relates to substituted 4-phenyltetrahydroisoquinoline compounds of the structure of formula I and pharmaceutical compositions comprising them wherein the R groups are herein defined. These are excellent inhibitors of the sodium-hydrogen exchanger (NHE), in particular of the sodium-hydrogen exchanger of subtype 3 (NHE3). As such these compounds are useful in the treatment of various disorders of the renal and respiratory systems such as acute or chronic renal failure, pulmonary complications, biliary function disorders, respiratory disorders such as snoring or sleep apneas and cardiovascular/central nervous system disorders such as stroke. More specifically, the present invention relates to substituted 4-phenyl-tetrahydroisoquinolines, derivatives thereof and compositions containing them formulated in combination with other compounds which also regulate the intracellular pH environment such as inhibitors of carbonic anhydrase and inhibitors of the transport systems that carry bicarbonate ions, such as of the sodium-bicarbonate co-transporter (NBC) or the sodium-dependent chloride-bicarbonate exchanger.

Substituted 4-phenyltetrahydroisoquinolines, pharmaceutical compositions thereof, methods for their preparation and therapeutic use

Substituted thienoimidazoles with a backbone structure of formula I or II: These substituted thienoimidazoles are useful in prevention or treatment of various disorders, including respiratory disorders.

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Bad Soden, Germany

Thomas Licher