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

Abstract

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-β peptide (Aβ), 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 pathologic process. We initially introduced a novel class of bridged aromatics referred tγ-secretase modulatoro 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. In this study, we report a large number of pharmacological studies and early assessment of toxicology characterizing a highly potent γ-secretase modulator (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 central nervous system 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 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.

γ-Secretase and its modulators: Twenty years and beyond

“…Chronic dosing of transgenic mice with BPN-15606 significantly reduced accumulation of Aβ plaques in both the hippocampus and cortex. Like previous reported BACE inhibitors [133], BPN-15606 treatment of 3-dimensional neuronal culture decreased total tau and phosphorylated pThr181 tau [132]. Based on in vivo pharmacokinetic profile of BPN-15606, sub micromolar plasma exposures of BPN-15606 expect to achieve a significant lowering of Aβ42 in human brain, thus requiring much lower doses than those reported for BMS-932481 and BMS-986133.…”

“…A unique GSM, BPN-15606, exhibited an IC50 of 7 nM and 17 nM to reduce Aβ42 and Aβ40 from cultured cells, with a concomitant increase of Aβ38 and no change in total Aβ [132]. BPN-15606 binds to an allosteric site within the γ-secretase complex and does not affect Notch cleavage at 25 μM.…”

Human-Induced Pluripotent Stem Cells and Herbal Small-Molecule Drugs for Treatment of Alzheimer’s Disease

“…BPN-15606 ( Figure 4g) inhibited the production of the Aβ1-42 and Aβ1-40 peptides, while facilitating the concomitant increase in Aβ1-38 and Aβ1-37 peptides production without inhibiting the γ-secretase-mediated proteolysis of Notch. BPN-15606 can lower Aβ42 levels significantly in the central nervous system of rats and mice [82]. Recent reports indicate that BPN-15606 is effective when administered prior to the severe pathological manifestations of AD [86].…”

“…GSM treatment of Alzheimer's disease is considered feasible. BPN-15606 is a highly potent GSM that is a candidate for human clinical trials [82].…”

NGP 555, a γ‐secretase modulator, shows a beneficial shift in the ratio of amyloid biomarkers in human cerebrospinal fluid at safe doses

“…Although GSMs represented a minority of the molecules tested in the clinic [16], to date most of these candidates have not succeeded because of compound toxicity based on structure or limited effectiveness to lower cerebrospinal fluid (CSF) amyloid biomarkers [32][33][34]. However, several GSMs are currently on the horizon and new discoveries of optimal chemical structures carry hope for the future of GSMs as therapeutics for AD [35][36][37][38][39][40][41][42][43][44]. One such molecule is NGP 555, with previous studies demonstrating the ability to favorably alter amyloid biomarkers and pathology in the brain while preventing cognitive decline preclinically.…”