PT  - JOURNAL ARTICLE
AU  - Steven L. Wagner
AU  - Kevin D. Rynearson
AU  - Steven K. Duddy
AU  - Can Zhang
AU  - Phuong D. Nguyen
AU  - Ann Becker
AU  - Uyen Vo
AU  - Deborah Masliah
AU  - Louise Monte
AU  - Justin B. Klee
AU  - Corinne M. Echmalian
AU  - Weiming Xia
AU  - Luisa Quinti
AU  - Graham Johnson
AU  - Jiunn H. Lin
AU  - Doo Y. Kim
AU  - William C. Mobley
AU  - Robert A. Rissman
AU  - Rudolph E. Tanzi
TI  - Pharmacological and Toxicological Properties of the Potent Oral <em>γ</em>-Secretase Modulator BPN-15606
AID  - 10.1124/jpet.117.240861
DP  - 2017 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 31--44
VI  - 362
IP  - 1
4099  - http://jpet.aspetjournals.org/content/362/1/31.short
4100  - http://jpet.aspetjournals.org/content/362/1/31.full
SO  - J Pharmacol Exp Ther2017 Jul 01; 362
AB  - 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.