Alzheimer's disease is characterized neuropathologically by an abundance of 1) neuritic plaques, which are primarily composed of a fibrillar 42 amino acid amyloid β peptide, as well as 2) neurofibrillary tangles composed of aggregates of hyperphosporylated tau. Elevations in the concentrations of the Aβ42 peptide in the brain, as a result of either increased production or decreased clearance are postulated to initiate and drive the AD pathological process. We initially introduced a novel class of bridged aromatics referred to as γ-secretase modulators that inhibited the production of the Aβ42 peptide and to a lesser degree the Aβ40 peptide while concomitantly increasing the production of the carboxyl-truncated Aβ38 and Aβ37 peptides. These modulators potently lower Aβ42 levels without inhibiting the γ-secretase-mediated proteolysis of Notch or causing accumulation of carboxyl-terminal fragments of APP. Herein we report a large number of pharmacological studies and early assessment of toxicology characterizing a highly potent GSM, (S)-N-(1-(4-fluorophenyl)ethyl)-6-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methylpyridazin-3-amine (BPN-15606). BPN-15606 displayed the ability to significantly lower Aβ42 levels in the CNS of rats and mice at doses as low as 5-10 mg/kg, significantly reduce Aβ neuritic plaque load in an AD transgenic mouse model and significantly reduce levels of insoluble Aβ42 and pThr181 tau in a 3D human neural cell culture model. Results from repeat-dose toxicity studies in rats and dose escalation/repeat dose toxicity studies in non-human primates have designated this GSM for 28-day IND-enabling GLP studies and positioned it as a candidate for human clinical trials.
- The American Society for Pharmacology and Experimental Therapeutics