Hydroxytriamides as potent γ-secretase inhibitors

Abstract Using a cell-based assay, we have identified optimal residues and key recognition elements necessary for inhibition of γ-secretase. An (S)-hydroxy group or 3,5-difluorophenylacetyl group at the amino terminus and N-methyltertiary amide moiety at the carboxy terminus provided potent γ-secretase inhibitors with an IC50

[1]  J. Treanor,et al.  Fenchylamine sulfonamide inhibitors of amyloid beta peptide production by the gamma-secretase proteolytic pathway: potential small-molecule therapeutic agents for the treatment of Alzheimer's disease. , 2000, Journal of medicinal chemistry.

[2]  D. Selkoe,et al.  Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity , 1999, Nature.

[3]  R. Rydel,et al.  Therapeutic approaches related to amyloid-beta peptide and Alzheimer's disease. , 1995, Journal of medicinal chemistry.

[4]  A. Nadin,et al.  High affinity, bioavailable 3-Amino-1,4-benzodiazepine-Based γ-Secretase inhibitors , 2003 .

[5]  E A Emini,et al.  Benzocycloalkyl amines as novel C-termini for HIV protease inhibitors. , 1991, Journal of medicinal chemistry.

[6]  F. D. Miller,et al.  Functional gamma‐secretase inhibitors reduce beta‐amyloid peptide levels in brain , 2000, Journal of neurochemistry.

[7]  Alfredo G. Tomasselli,et al.  Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity , 1999, Nature.

[8]  D. Selkoe,et al.  A Substrate-Based Difluoro Ketone Selectively Inhibits Alzheimer's γ-Secretase Activity , 1998 .

[9]  D. Selkoe,et al.  Alzheimer's Disease--Genotypes, Phenotype, and Treatments , 1997, Science.

[10]  M. Wolfe,et al.  Secretase targets for Alzheimer's disease: identification and therapeutic potential. , 2001, Journal of medicinal chemistry.

[11]  D. Selkoe,et al.  Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production , 1992, Nature.

[12]  G. Glenner,et al.  Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein , 1984 .

[13]  S. Younkin,et al.  An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. , 1994, Science.

[14]  Hugo Vanderstichele,et al.  Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein , 1998, Nature.

[15]  R. Barbour,et al.  Purification and cloning of amyloid precursor protein β-secretase from human brain , 1999, Nature.

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

[17]  A. Nadin,et al.  Synthesis and γ-secretase activity of APP substrate-based hydroxyethylene dipeptide isosteres , 2003 .

[18]  M. Wolfe,et al.  The Search for γ-Secretase and Development of Inhibitors , 2002 .

[19]  D. Selkoe,et al.  Alzheimer's Disease: A Central Role for Amyloid , 1994, Journal of neuropathology and experimental neurology.

[20]  Allan I. Levey,et al.  Familial Alzheimer's Disease–Linked Presenilin 1 Variants Elevate Aβ1–42/1–40 Ratio In Vitro and In Vivo , 1996, Neuron.

[21]  R. Conradi,et al.  The Influence of Peptide Structure on Transport Across Caco-2 Cells. II. Peptide Bond Modification Which Results in Improved Permeability , 1992, Pharmaceutical Research.

[22]  J. Treanor,et al.  Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. , 1999, Science.

[23]  Graeme Irvine Stevenson,et al.  L-685,458, an Aspartyl Protease Transition State Mimic, Is a Potent Inhibitor of Amyloid β-Protein Precursor γ-Secretase Activity , 2000 .

[24]  D. Selkoe,et al.  Evidence that the 42- and 40-amino acid forms of amyloid beta protein are generated from the beta-amyloid precursor protein by different protease activities. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[25]  S. Younkin,et al.  Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice , 1996, Science.

[26]  E. Parker,et al.  Biochemical characterization of the gamma-secretase activity that produces beta-amyloid peptides. , 2001, Biochemistry.

[27]  J. Hardy,et al.  New insights into the genetics of Alzheimer's disease. , 1996, Annals of medicine.

[28]  Dennis J. Selkoe.  Physiological production of the β-amyloid protein and the mechanism of Alzheimer's disease , 1993, Trends in Neurosciences.