Discovery of novel 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine derivatives as γ-secretase modulators (Part 2).

Abstract γ-Secretase modulators (GSMs), which lower pathogenic amyloid beta (Aβ) without affecting the production of total Aβ or Notch signal, have emerged as a potential therapeutic agent for Alzheimer’s disease (AD). A novel series of 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3- a ]pyridine derivatives was discovered and characterized as GSMs. Optimization of substituents at the 8-position of the core scaffold using ligand-lipophilicity efficiency (LLE) as a drug-likeness guideline led to identification of various types of high-LLE GSMs. Phenoxy compound ( R )- 17 exhibited especially high LLE as well as potent in vivo Aβ 42 -lowering effect by single administration. Furthermore, multiple oral administration of ( R )- 17 significantly reduced soluble and insoluble brain Aβ 42 , and ameliorated cognitive deficit in novel object recognition test (NORT) using Tg2576 mice as an AD model.