Pharmacological and Toxicological Properties of the Potent Oral γ -Secretase Modulator BPN-15606

Alzheimer's disease (AD) is characterized neuropathologically by an abundance of 1) neuritic plaques, which are primarily composed of a fibrillar 42-amino-acid amyloid- peptide (A ), as well as 2) neurofibrillary tangles composed of aggregates of hyperphosporylated tau. Elevations in the concentrations of the A 42 peptide in the brain, as a result of either increased production or decreased clearance, are postulated to initiate and drive the AD pathologic process. We initially introduced a novel class of bridged aromatics referred t -secretase modulatoro as -secretase modulators that inhibited the production of the A 42 peptide and to a lesser degree the A 40 peptide while concomitantly increasing the production of the carboxyl-truncated A 38 and A 37 peptides. These modulators potently lower A 42 levels without inhibiting the -secretase-mediated proteolysis of Notch or causing accumulation of carboxyl-terminal fragments of APP. In this study, we report a large number of pharmacological studies and early assessment of toxicology characterizing a highly potent -secretase modulator (GSM), ( )- -(1-(4-fluorophenyl)ethyl)-6-(6-methoxy-5-(4-methyl-1 -imidazol-1-yl)pyridin-2-yl)-4-methylpyridazin-3-amine (BPN-15606). BPN-15606 displayed the ability to significantly lower A 42 levels in the central nervous system of rats and mice at doses as low as 5-10 mg/kg, significantly reduce A neuritic plaque load in an AD transgenic mouse model, and significantly reduce levels of insoluble A 42 and pThr181 tau in a three-dimensional human neural cell culture model. Results from repeat-dose toxicity studies in rats and dose escalation/repeat-dose toxicity studies in nonhuman primates have designated this GSM for 28-day Investigational New Drug-enabling good laboratory practice studies and positioned it as a candidate for human clinical trials.