STRUCTURE-BASED DESIGN AND SYNTHESIS OF NOVEL INHIBITORS OF BETA-SITE AMYLOID PRECURSOR PROTEIN CLEAVING ENZYME 1

Alzheimer’s disease (AD) continues to plague the healthcare community as a serious healthcare crisis. Currently there fails to be an effective FDA approved drug that can treat the underlying mechanisms of the disease. Pathologically the disease is characterized by the accumulation of neurotoxic amyloid-b(Ab) plaques within a diseased patient’s brain. These plaques are widely accepted to be generated by the sequential proteolytic cleavage of amyloid precursor protein (APP) by b-secretase (BACE1, memapsin 2) and g-secretase. Numerous biochemical markers suggest that BACE1 is a viable target for AD drug development. Since the cloning and expression of BACE1 there has been an explosion of drug development efforts that have consisted of peptidomimetic-based and non-peptide-based inhibitors. These efforts have led to 13 BACE1 drug candidates some of which have made it to advanced stages of clinical trials. Unfortunately, an effective and tolerable BACE1 drug candidate continues to be rather elusive to the medicinal chemistry community. GRL-8234 is a potent BACE1 inhibitor that has been extensively shown to be tolerable during several short-term and long-term in vivo studies. The scaffold of GRL-8234 provides a suitable template for further lead development. Namely the P1’ 3-methoxy-benzylamine is of particular interest due to the advantageous interactions in the flap region of BACE1 that can be achieved by incorporation of substitution at the benzylic position. In the same way, the meta-substituent of the benzylamine P1’ ligand was investigated to probe the hydrophobic interactions in the S1’-S2’ binding pocket. A novel class of BACE1 inhibitors containing P1’ spirocyclic benzylamine derivatives were designed, synthesized and evaluated for their inhibitory activity against BACE1. In the process of preparing the aforementioned BACE1 inhibitors a method was established to be able to incorporate the desired 3,5-difluorophenyl methyl transition state isostere by utilizing an ester-derived Ti-enolate to access optically pure syn- and anti-aldol adducts as a key step. Additionally, a novel stereoselective method was established to afford heterospirocyclic benzylamines by utilizing a diastereoselective allyl grignard addition to optically pure a-silyloxy N-sulfinyl ketimines as a key step. Biological evaluation of these novel BACE1 inhibitors has been fruitful and continues to be ongoing.