3,4-Fused cyclohexyl sulfones as γ-secretase inhibitors

Abstract The 3,4-fused sulfamides, sulfonamides and sulfone have been identified as highly potent γ-secretase inhibitors. Evaluation of the SAR of substitution within these series has allowed the identification of a range of compounds which significantly reduce brain Aβ in transgenic mouse models and thus have potential as possible treatments for Alzheimer’s disease.

[1]  M. Shearman,et al.  Quantitation of amyloid-β peptides in biological milieu using a novel homogeneous time-resolved fluorescence (HTRF) assay , 2000, Journal of Neuroscience Methods.

[2]  D. Price,et al.  Introduction and expression of the 400 kilobase precursor amyloid protein gene in transgenic mice , 1993, Nature Genetics.

[3]  J. Hardy,et al.  Alzheimer's disease: the amyloid cascade hypothesis. , 1992, Science.

[4]  A. Nadin,et al.  Quantitative Measurement of Changes in Amyloid-β(40) in the Rat Brain and Cerebrospinal Fluid following Treatment with the γ-Secretase Inhibitor LY-411575 [N2-[(2S)-2-(3,5-Difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-l-alaninamide] , 2005, Journal of Pharmacology and Experimental Therapeutics.

[5]  M. Tsubuki,et al.  Construction of a chiral quaternary carbon center by enantioselective deprotonation: Application to the formal synthesis of (+)-α-cuparenone , 1993 .

[6]  A. Nadin,et al.  Catalytic Site-Directed γ-Secretase Complex Inhibitors Do Not Discriminate Pharmacologically between Notch S3 and β-APP Cleavages , 2003 .

[7]  Timothy Harrison,et al.  Aryl sulfones : A new class of γ-secretase inhibitors , 2005 .

[8]  I. Churcher,et al.  gamma-Secretase as a target for drug intervention in Alzheimer's disease. , 2004, Current opinion in drug discovery & development.

[9]  D. M. Hodgson,et al.  Overview of Organolithium-Ligand Combinations and Lithium Amides for Enantioselective Processes , 2003 .

[10]  Euan R. Kay,et al.  4-Substituted cyclohexyl sulfones as potent, orally active γ-secretase inhibitors , 2006 .