Use of selective gaba a alpha 5 negative allosteric modulators for the treatment of central nervous system conditions

Abstract

The present invention relates to the pharmaceutical use of selective GABA A α5 negative allosteric modulators for the treatment, prevention and/or delay of progression of central nervous system (CNS) conditions related to excessive GABAergic inhibition in the brain.

1 . A method of treating or delaying the progression of Central Nervous System (CNS) conditions related to excessive GABAergic inhibition in the cortex and hippocampus comprising administering to a subject having such condition a therapeutically effective amount of a GABA A α5 negative allosteric modulator, wherein the GABA A α5 negative allosteric modulator is (1,1-Dioxo-1,6-thiomorpholin-4-yl)-{6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-methanone
 or a pharmaceutically acceptable salt thereof and wherein said CNS condition is cognitive deficits in autism, cognitive deficits in neurofibromatosis type I or cognitive deficits after stroke. 
 
     
     
         2 . The method of  claim 1 , wherein the excessive GABAergic inhibition in the cortex and hippocampus is caused by neurodevelopmental defects. 
     
     
         3 . The method of  claim 1 , wherein the CNS conditions are caused by neurodevelopmental defects which result in excessive GABAergic inhibition in the cortex and hippocampus. 
     
     
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         9 . The method of  claim 1 , wherein said GABA A α5 negative allosteric modulator binds to human GABA A α5β3γ2 receptor subtype with a binding selectivity of a factor of 10 or more as compared to binding affinities to human GABA A α1β2/3γ2, α2β3γ2 and α3β3γ2 receptor subtypes. 
     
     
         10 . The method of  claim 1 , wherein said GABA A α5 negative allosteric modulator exhibits a functional selectivity by acting as inverse agonist at human GABA A α5β3γ2 receptor subtype by reducing the effect of GABA by more than 30% and in addition affecting the effect of GABA at human GABA A α1β2/3γ2, α2β3γ2 and α3β3γ2 receptor subtypes by less than 15%. 
     
     
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