Novel gamma-secretase inhibitors discovered by library screening of in-house synthetic natural product intermediates.

Screening of our in-house compound library comprised of intermediates of natural product synthesis projects resulted in discovering two novel gamma-secretase inhibitors, which coincidently had similar moieties, that is, cyclohexenone and two aryl groups arranged on the core six-membered ring. Structure-activity relationship studies of these compounds were also developed.

[1]  David W. Smith,et al.  Dynamics of β-Amyloid Reductions in Brain, Cerebrospinal Fluid, and Plasma of β-Amyloid Precursor Protein Transgenic Mice Treated with a γ-Secretase Inhibitor , 2005, Journal of Pharmacology and Experimental Therapeutics.

[2]  T. Kan,et al.  N-CARBOALKOXY-2-NITROBENZENESULFONAMIDES : A PRACTICAL PREPARATION OF N-BOC-, N-ALLOC-, AND N-CBZ-PROTECTED PRIMARY AMINES , 1999 .

[3]  T. Ueda,et al.  Stereocontrolled total synthesis of (+)-vinblastine. , 2002, Journal of the American Chemical Society.

[4]  N. Chida,et al.  Synthesis of optically active substituted cyclohexenones from carbohydrates by catalytic Ferrier rearrangement , 1991 .

[5]  T. Iwatsubo,et al.  Highly efficient synthesis of medium-sized lactams via intramolecular Staudinger–aza-Wittig reaction of ω-azido pentafluorophenyl ester: synthesis and biological evaluation of LY411575 analogues , 2004 .

[6]  W. H. Jordan,et al.  Adipsin, a Biomarker of Gastrointestinal Toxicity Mediated by a Functional γ-Secretase Inhibitor* , 2003, Journal of Biological Chemistry.

[7]  T. Iwatsubo,et al.  The role of presenilin cofactors in the γ-secretase complex , 2003, Nature.

[8]  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.

[9]  T. Iwatsubo,et al.  The inhibition of gamma-secretase as a therapeutic approach to Alzheimer's disease. , 2004, Drug news & perspectives.

[10]  H. Tokuyama,et al.  Reduction of ethanethiol esters to aldehydes , 2002 .

[11]  T. Iwatsubo,et al.  Parallel synthesis of DAPT derivatives and their γ-secretase-inhibitory activity , 2004 .

[12]  H. Fuwa,et al.  Synthetic studies on antascomicin A: construction of the C18–C34 fragment , 2004 .

[13]  T. Iwatsubo,et al.  Solid-phase synthesis of photoaffinity probes: highly efficient incorporation of biotin-tag and cross-linking groups. , 2003, Chemical communications.

[14]  T. Iwatsubo,et al.  Sulindac Sulfide Is a Noncompetitive γ-Secretase Inhibitor That Preferentially Reduces Aβ42 Generation* , 2003, The Journal of Biological Chemistry.

[15]  S. Wagner,et al.  Reductions in β-amyloid concentrations in vivo by the γ-secretase inhibitors BMS-289948 and BMS-299897 , 2005 .

[16]  O. Mitsunobu The Use of Diethyl Azodicarboxylate and Triphenylphosphine in Synthesis and Transformation of Natural Products , 1981 .

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

[18]  Jay S. Fine,et al.  Chronic Treatment with the γ-Secretase Inhibitor LY-411,575 Inhibits β-Amyloid Peptide Production and Alters Lymphopoiesis and Intestinal Cell Differentiation* , 2004, Journal of Biological Chemistry.

[19]  T. Lanz,et al.  Studies of Aβ Pharmacodynamics in the Brain, Cerebrospinal Fluid, and Plasma in Young (Plaque-Free) Tg2576 Mice Using the γ-Secretase Inhibitor 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 (LY-411575) , 2004, Journal of Pharmacology and Experimental Therapeutics.

[20]  T. Kan,et al.  Ns strategies: a highly versatile synthetic method for amines. , 2004, Chemical communications.

[21]  T. Saegusa,et al.  Synthesis of .alpha.,.beta.-unsaturated carbonyl compounds by palladium(II)-catalyzed dehydrosilylation of silyl enol ethers , 1978 .

[22]  Francois Pognan,et al.  Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.