Aminothiazole Secretase Inhibitors

 A new γ-secretase modulators with an Aminothiazole core starting from a HTS hit is disclosed .  Also, synthesis and SAR of this series are discussed.

These novel compounds demonstrate moderate to good in vitro potency in inhibiting amyloid beta (Aβ) peptide production.

Overall γ-secretase is not inhibited but the formation of the aggregating, toxic Aβ42 peptide is shifted to smaller non-aggregating Aβ peptides. Compound 15 reduced brain Aβ42 in vivo in APPSwe transgenic mice at 30 mg/kg p.o.