Identification of a new class of potent bace-1 inhibitors through scaffold hopping

Due to the constant growth in the number of patients affected with Alzheimer disease (AD), the need of effective drugs able to stop the neuronal degeneration is increasing. Considering the therapeutic necessity of new molecules, we focused our attention in designing new BACE-1 inhibitors with good pharmacokinetic and pharmacodynamics properties, able to cross the bloodbrain barrier. Using a scaffold hopping approach, we moved from a known BACE-1 ligand with good activity but poor values of MW and tPSA to a new aminothiazole scaffold with improved properties. Further optimization, aimed to improve pharmacokinetic properties as well as metabolic stability, led to the synthesis of an aminothiadiazole scaffold library of compounds that have been tested to assess their ability to inhibit BACE-1 activity.