Discovery of brain permeable 2-Azabicyclo[2.2.2]octane sulfonamides as a novel class of presenilin-1 selective γ-secretase inhibitors

This paper describes the rational design, synthesis, structure-activity relationship (SAR), and biological profile of presenilin-1 (PSEN-1) complex selective gamma-secretase inhibitors, assessed for selectivity using a unique set of four gamma-secretase subtype complexes. A set of known PSEN-1 selective gamma-Secretase inhibitors (GSIs) was analyzed to understand the pharmacophoric features required for selective inhibition. Conformational modeling suggests that a characteristic 'U' shape orientation between aromatic sulfone/sulfonamide and aryl ring is crucial for PSEN-1 selectivity and potency. Using these insights, a series of brain-penetrant 2-azabicyclo [2,2,2]octane sulfonamides was devised and synthesized as a new class of PSEN-1 selective inhibitors. Compounds 13c and 13k displayed high potency towards PSEN1-APH1B complex but moderate selectivity towards PSEN2 complexes. However, compound (+)-13b displayed low nanomolar potency towards the PSEN1-APH1B complex, little (similar to 4-fold) selectivity towards PSEN1-APH1A, and high selectivity (>350-fold) versus PSEN2 complexes. Excellent brain penetration, no significant CYP inhibition, or cardiotoxicity, good solubility, and permeability make (+)-13b an excellent candidate for further lead optimization.