Use of a RAR-gamma-specific agonist ligand for increasing the rate of apoptosis

Abstract

A method for increasing the rate of apoptosis in at least one cell population in which apoptosis is induced by activating receptors of the RAR-γ type, the method comprising exposing the cell population to an effective amount of at least one agonist ligand which is specific for receptors of the RAR-γ type to increase the rate of apoptosis.

What is claimed is:  
     
         1 . A method for increasing the rate of apoptosis in at least one cell population in which apoptosis is induced by activating receptors of the RAR-γ type, said method comprising exposing said cell population to an effective amount of at least one agonist ligand which is specific for receptors of the RAR-γ type to increase the rate of apoptosis, with the proviso that said agonist ligand is not 6-3-(1-adamantyl)-4-hydroxyphenyl-2-naphthanoic acid, said method being used to treat a precancerous condition linked to an inadequate rate of apoptosis.  
     
     
         2 . The method according to    claim 1   , wherein said precancerous condition is actinic keratosis.  
     
     
         3 . A method for increasing the rate of apoptosis in at least one cell population in which apoptosis is induced by activating receptors of the RAR-γ type, said method comprising exposing said cell population to an effective amount of at least one agonist ligand which is specific for receptors of the RAR-γ type to increase the rate of apoptosis, wherein said agonist ligand which is specific for receptors of the RAR-γ type exhibits a ratio R which is greater than or equal to 50, wherein R is the dissociation constant of the ligand for receptors of the RAR-α type relative to receptors of the RAR-γ type, with the proviso that said agonist ligand is not 6-3-(1-adamantyl)-4-hydroxyphenyl-2-naphthanoic acid, said method being used to treat a precancerous condition linked to an inadequate rate of apoptosis.  
     
     
         4 . The method according to    claim 3   , wherein said precancerous condition is actinic keratosis.  
     
     
         5 . A method for increasing the rate of apoptosis in at least one cell population in which apoptosis is induced by activating receptors of the RAR-γ type, said method comprising exposing said cell population to an effective amount of at least one agonist ligand which is specific for receptors of the RAR-γ type to increase the rate of apoptosis, said agonist ligand being selected from the group consisting of (E)-4-(1-hydroxyl-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-propenyl)benzoic acid, 4-[(E)-2-(3-(1-adamantyl)-4-hydroxyphenyl)-1-propenyl]benzoic acid, 5′,5′,8′,8′-tetramethyl-5′,6′,7′,8′-tetrahydro-[2,2′]binaphthalenyl-6-carboxylic acid, 2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzo[b]thiophene-6-carboxylic acid, 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphtho[ 2,3-b]thiophen-2-yl)benzoic acid, 6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carbonyl)naphthalene-2-carboxylic acid, 3,7-dimethyl-7-(1,2,3,4-tetrahydro-1,4a,9b-trimethyl-1,4-methano-dibenzofuran-8-yl)-2,4,6-heptatrienoic acid, 6-(1,2,3,4-tetrahydro-1,4a,9b-trimethyl-1,4-methano-dibenzofuran-8-yl)naphthalene-2-carboxylic acid, 6-[ hydroxyimino-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)methyl]naphthalene-2-carboxylic acid, 4-[(6-hydroxy-7-(1-adamantyl)-2-naphthyl]benzoic acid, 5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydroanthracen-2-yl)thiophene-2-carboxylic acid, (−)-6-[hydroxy-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl] naphthalene-2-carboxylic acid, 6-(3-adamantan-1-yl-4-prop-2-ynyloxyphenyl)naphthalene-2-carboxylic acid, 4-[(2-oxo-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethoxy]benzoic acid, 4-[2-oxo-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)acetylamino]benzoic acid, 4-[ 2-fluoro-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)acetylamino]benzoic acid, 6-[3-(1-adamantyl-4-(2-hydroxypropyl)phenyl]-2-naphthoic acid, 5-[3-oxo-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)propenyl]thiophene-2-carboxylic acid, 6-[3-(1-adamantyl-4-(2,3-dihydroxypropyl)phenyl]-2-naphthoic acid, 4-[3-hydroxy-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid, 4-[3-oxo-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)prop-1-ynyl]benzoic acid, 4[ (3-(1-methylcyclohexyl)-4-hydroxyphenyl)ethenyl]-benzoic acid, 4-[(E)2-(3-(1-adamantyl)-4-hydroxyphenyl)ethenyl] benzoic acid, 4-[3-(1-adamantyl)-4-hydroxyphenylethynyl)benzoic acid, 5-[3-(1-adamantyl)-4-hydroxyphenylethynyl]-2-thiophenecarboxylic acid, 5-[3-(1-adamantyl)-4-methoxyphenylethynyl]-2-thiophenecarboxylic acid, 4-[2-(3-tert-butyl-4-methoxyphenyl)propenyl]benzoic acid, 4-{2-[4-methoxy-3-(1-methylcyclohexyl)phenyl]-propenyl} benzoic acid, 6-[3-(1-adamantyl)-4-(3-methoxy-2-hydroxypropyl)phenyl]-2-naphthoic acid, 2-hydroxy-4-[ 3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid, 6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)naphthalene-2-carboxylic acid, 6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylsulphanyl)naphthalene-2-carboxylic acid, 4-[2-propoxyimino-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)acetylamino]benzoic acid, 6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylamino)naphthalene-2-carboxylic acid, 1-methyl-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydroanthracen-2-yl)-1H-pyrrole-2-carboxylic acid, 2-methoxy-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydroanthracen-2-yl)benzoic acid, 4-[2-nonyloxyimino-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)acetylamino]benzoic acid, (−)-2-hydroxy-4-[3-hydroxy-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)prop-1-ynyl] benzoic acid, (+)-2-hydroxy-4-[3-hydroxy-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)prop-1-ynyl]benzoic acid, 2-hydroxy-4-[3-hydroxy-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)but-1-ynyl]benzoic acid, 6-(3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)-naphthalene-2-carboxylic acid, 3-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2H-1-benzopyran]-7-carboxylic acid, 4-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)prop-1-ynyl]benzoic acid, 4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)prop-1-ynyl] benzoic acid, 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]salicylic acid, 4-[ {3-(1-adamantyl)-4-(2-hydroxyethyl)phenyl}ethynyl]-benzoic acid and 4-[{3-(1-adamantyl)-4-(3-hydroxypropyl)phenyl} ethynyl]benzoic acid, said method being used to treat a precancerous condition linked to an inadequate rate of apoptosis.  
     
     
         6 . The method according to    claim 5   , wherein said precancerous condition is actinic keratosis.  
     
     
         7 . A method for increasing the rate of apoptosis in at least one cell population in which apoptosis is induced by activating receptors of the RAR-γ-type, said method comprising exposing said cell population to an effective amount of at least one agonist ligand which is specific for receptors of the RAR-γ type to increase the rate of apoptosis, said agonist ligand being selected from the group consisting of 6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carbonyl)-naphthalene-2-carboxylic acid, 6-(1,2,3,4-tetrahydro-1,4a,9b-trimethyl-1,4-methanodibenzofuran-8-yl)-naphthalene-2-carboxylic acid, 6-[hydroxyimino-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl] naphthalene-2-carboxylic acid, 5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydroanthracen-2-yl)-thiophene-2-carboxylic acid, (−)-6-[hydroxy-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-methyl] naphthalene-2-carboxylic acid, 6-[3-(1-adamantyl-4-(2-hydroxypropyl)phenyl]-2-naphthoic acid, 6-[3-(1-adamantyl-4-(2,3-dihydroxypropyl)phenyl]-2-naphthoic acid, 4-[3-(1-adamantyl)-4-hydroxyphenylethynyl] benzoic acid, 5-[3-(1-adamantyl)-4-hydroxyphenylethynyl]-2-thiophenecarboxylic acid, 5-[ 3-(1-adamantyl)-4-methoxyphenylethynyl]-2-thiophenecarboxylic acid, 6-[3-(1-adamantyl)-4-(3-methoxy-2-hydroxypropyl)phenyl]-2-naphthoic acid, 1-methyl-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-anthracen-2-yl)-1H-pyrrole-2-carboxylic acid, (−)-2-hydroxy-4-[3-hydroxy-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)prop-1-ynyl]benzoic acid and 2-hydroxy-4-[3-hydroxy-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)but-1-ynyl)benzoic acid, said method being used to treat a precancerous condition linked to an inadequate rate of apoptosis.  
     
     
         8 . The method according to    claim 7   , wherein said precancerous condition is actinic keratosis.  
     
     
         9 . The method according to    claim 1   , wherein said agonist ligand is used in combination with a pharmaceutically acceptable carrier.  
     
     
         10 . The method according to    claim 3   , wherein said agonist ligand is used in combination with a pharmaceutically acceptable carrier.  
     
     
         11 . The method according to    claim 5   , wherein said agonist ligand is used in combination with a pharmaceutically acceptable carrier.  
     
     
         12 . The method according to    claim 7   , wherein said agonist ligand is used in combination with a pharmaceutically acceptable carrier.