Abstract: This invention relates to determining the three-dimensional structure of the cytosolic domain of phospholamban (PLB) and its active site from NMR data of sufficiently high resolution for the three-dimensional structure determination. The invention also relates to methods for rational drug design enabling the design of phospholamban inhibitors based on using the three-dimensional structure data provided on computer readable media, as analyzed on a computer system having suitable computer algorithms. The invention also relates to phospholamban inhibiting compounds with certain structural, physicochemical and spatial characteristics that allow for the interaction of said compounds with specific residues of the active site of phospholamban.

Abstract: Therapeutically active compounds of formula (I): in which R1 to R4 means hydrogen, alkyl, alkenyl, aryl, arylalkyl, carboxyalkyl, hydroxyalkyl or halogenalkyl, or R2 and R3 form a ring of 5-7 carbon atoms, R5 to R9 means hydrogen, alkyl, alkenyl, aryl, arylalkyl, acyl, hydroxy, alkoxy, alkoxycarbonyl, amino, acylamino, alkylamino, aryloxy, halogen, cyano, nitro, carboxy, alkylsufonyl, sulfonamido or trifluoromethyl, wherein each aryl residue defined above by itself or as a part of another group may be substituted, and pharmaceutically acceptable salts and esters thereof. The compounds increase the calcium sensitivity of contractile proteins of the cardiac muscle and are thus useful in the treatment of congestive heart failure.

Abstract: Therapeutically active compounds of formula (I) in which R1 to R4 means hydrogen, alkyl, alkenyl, aryl, arylalkyl, carboxyalkyl, hydroxyalkyl or halogenalkyl, or R2 and R3 form a ring of 5-7 carbon atoms. R5 to R9 means hydrogen, alkyl, alkenyl, aryl, arylalkyl, acyl, hydroxy, alkoxy, alkoxycarbonyl, amino, acylamino, alkylamino, aryloxy, halogen, cyano, nitro, carboxy, alkylsulfonyl, sulfonamido or trifluoromethyl, wherein each aryl residue defined above by itself or as a part of another group may be substituted, and pharmaceutically acceptable salts and esters thereof. The compounds increase the calcium sensitivity of contractile proteins of the cardiac muscle and are thus useful in the treatment of congestive heart failure.

Abstract: This invention relates to determining the three-dimensional structure of the cytosolic domain of phospholamban (PLB) and its active site from NMR data of sufficiently high resolution for the three-dimensional structure determination. The invention also relates to methods for rational drug design enabling the design of phospholamban inhibitors based on using the three-dimensional structure data provided on computer readable media, as analyzed on a computer system having suitable computer algorithms. The invention also relates to phospholamban inhibiting compounds with certain structural, phsicochemical and spatial characteristics that allow for the interaction of said compounds with specific residues of phospholamban.

Abstract: A method for obtaining direct dilatation of the coronary arteries by administering a therapeutically effective amount of a phospholamban inhibitor is described. Compounds which are effective in relieving the inhibitory effects of phospholamban on cardiac sarcoplasmic reticulum Ca2+-ATPase are also described.

Abstract: A method for the prevention and treatment of stunning of the heart subsequent to ischemia-reperfusion is described. The method comprises administering a therapeutically effective amount of a phospholamban inhibitor to a patient. Phospholamban inhibitors relieve the inhibitory effect of phospholamban on cardiac sarcoplasmic reticulum Ca.sup.2+ -ATPase.

Abstract: A method for the treatment of neurohumoral imbalance caused by alterations of cardiac function to prevent the development of heart failure comprises administering an effective amount of (R)-?4-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)phenyl!acetamide to a mammal in need of such treatment.

Abstract: A method for the treatment of neurohumoral imbalance caused by alterations of cardiac function to prevent the development of heart failure comprises administering an effective amount of (R)-N-[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]acetamide to a mammal in need of such treatment.