We will present the design and synthesis of small and potent γ-Secretase Modulators (GSMs) starting from our most profiled lead compound RO6800020 using  sequential structural replacements to improve desired properties, safety and potency.

Importantly, we also describe a novel phenyl ring bioisostere that affects dramatically the compound properties.

Our in-depth lead optimization strategy culminated in series of potent and in vivo active γ-secretase modulators devoid of safety flags with one compound being selected as an advanced candidate