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

Pharmacological and Toxicological Properties of the Potent Oral γ-Secretase Modulator BPN-15606.
Author Information (click to view)

Wagner SL, Rynearson KD, Duddy SK, Zhang C, Nguyen PD, Becker A, Vo U, Masliah D, Monte L, Klee JB, Echmalian CM, Xia W, Quinti L, Johnson G, Lin JH, Kim DY, Mobley WC, Rissman RA, Tanzi RE,


Wagner SL, Rynearson KD, Duddy SK, Zhang C, Nguyen PD, Becker A, Vo U, Masliah D, Monte L, Klee JB, Echmalian CM, Xia W, Quinti L, Johnson G, Lin JH, Kim DY, Mobley WC, Rissman RA, Tanzi RE, (click to view)

Wagner SL, Rynearson KD, Duddy SK, Zhang C, Nguyen PD, Becker A, Vo U, Masliah D, Monte L, Klee JB, Echmalian CM, Xia W, Quinti L, Johnson G, Lin JH, Kim DY, Mobley WC, Rissman RA, Tanzi RE,

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The Journal of pharmacology and experimental therapeutics 2017 04 17362(1) 31-44 doi 10.1124/jpet.117.240861
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.

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