Novel Soluble Gamma-Secretase Modulators for the Treatment of Alzheimer’s Disease Identification of the Molecular Target of Potent Gamma-Secretase Modulators

The goal of this project is to identify a series of highly potent gamma-secretase modulators able to lower Abeta₄₂ and Abeta₄₀ production while concomitantly increasing the less toxic production of Abeta₃₈ without measurably affecting gamma-secretase-mediated processing of the Notch 1 receptor (which is very important in a variety of cellular processes for cell-to-cell communication).

Dr. Steven Wagner and his fellow researchers recently discovered two structurally related series of gamma-secretase modulators (AGSMs and SGSMs) with potencies more than a thousandfold superior to tarenflurbil and many of the NSAID-like carboxylic acid-containing GSMs. The first series of these aryl 2-aminothiazole GSMs (AGSMs) are small molecules that bind directly to gamma-secretase, decreasing Abeta₄₂ and Abeta₄₀ levels while concomitantly increasing Abeta₃₈ and Abeta₃₇ levels without affecting gamma-secretase-mediated enzymatic processing of other known substrates, such as Notch-1.

AGSMs were shown to be efficacious in vivo for lowering the levels of Abeta₄₂ and Abeta₄₀ in both the plasma and brain of APP transgenic mice. Chronic efficacy studies revealed that one AGSM (compound 4) dramatically attenuated AD-like pathology in the Tg2576 APP transgenic mouse model. In addition, unlike the GSls, the AGSMs, by virtue of the fact they do not inhibit gamma-secretase, do not show Notch-related side effects that invariably appear in rodents and mice when treated chronically with GSls (e.g., no evidence of intestinal goblet cell hyperplasia). However, the very poor aqueous solubility of these AGSMs (<0.1 micromolar at neutral pH) may significantly compromise their further preclinical development due to the difficulties in achieving the escalated supraefficacious exposures necessary for safety and toxicity studies required for advanced preclinical development with such poorly soluble compounds.

More recently, the researchers discovered a second series of highly potent GSMs that have significantly improved physicochemical properties (e.g., aqueous solubilities at neutral pH) compared to the previously described AGSM series. These two structurally related series, as may be expected, behave similarly with respect to their effects on APP processing in steady- state cell-based assays. Both GSM series are able to lower Abeta₄₂ and Abeta₄₀ production while concomitantly increasing Abeta₃₈ production without measurably affecting gamma-secretase- mediated processing of another known gamma-secretase substrate, namely, the Notch 1 receptor.