Currently there are no disease modifying therapies for the treatment of Alzheimer's disease (AD). Based on the amyloid hypothesis, reduction of β-amyloid (Aβ) peptide monomers, oligomers and/or plaques by inhibition of the aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (β-secretase or BACE1) has the potential to slow or halt the progression of this devastating disease. In our pursuit of brain penetrant BACE inhibitors, we started from a fragment-based hit and made intensive use of X-ray crystallography and <i>in vivo</i> screening for central Aβ lowering in rodents to guide the development of structure activity relationships (SAR). In this poster, we will present our discovery of a novel iminoheterocylic scaffold, and the design, synthesis, and SAR of a series of potent BACE1 inhibitors based on this scaffold. These inhibitors exhibited robust reduction of central Aβ in a rat pharmacodynamic model through their optimized physicochemical properties and pharmacokinetic profiles. From these efforts, we identified MK-8931, a potent and selective BACE inhibitor that is undergoing clinical evaluation in two Phase 3 trials in mild-to-moderate and prodromal AD patients. In this poster, we will also present details of the preclinical profile of MK-8931 along with Phase 1 clinical data.

Structure-activity relationships of iminoheterocyclic BACE1 inhibitors: Discovery of MK-8931 for the treatment of Alzheimer's disease

249th National Meeting (2015)

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