The identification of centrally efficacious β-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) has historically been thwarted by an inability to maintain alignment of potency, brain availability, and desired absorption, distribution, metabolism, and excretion (ADME) properties. In this paper, we describe a series of truncated, fused thioamidines that are efficiently selective in garnering BACE1 activity without simultaneously inhibiting the closely related cathepsin D or negatively impacting brain penetration and ADME alignment, as exemplified by 36. Upon oral administration, these inhibitors exhibit robust brain availability and are efficacious in lowering central Amyloid β (Aβ) levels in mouse and dog. In addition, chronic treatment in aged PS1/APP mice effects a decrease in the number and size of Aβ-derived plaques. Most importantly, evaluation of 36 in a 2-week exploratory toxicology study revealed no accumulation of autofluorescent material in retinal pigment epithelium or histology findings in the eye, issues observed with earlier BACE1 inhibitors.

N-Aryl pyrazoles were prepared from anilines in a three step telescoped approach. An aniline was diazotized to give the diazonium fluoroborate, followed by reduction with tin(II) chloride to give the corresponding hydrazine, which in turn reacted with a ketoenamine to give the N-aryl pyrazole. The deprotection of the methyl ether was accomplished with PhBCl 2 to give the final product. The continuous flow methodology was used to minimize accumulation of the highly energetic and potentially explosive diazonium salt and hydrazine intermediates to enable the safe scale-up of N-aryl pyrazoles. The heterogeneous reaction mixture was successfully handled in both lab scale and production scale. A continuous extraction was employed to remove organic impurities from the diazotization step, which eliminated the need for chromatography in the purification of the final N-aryl pyrazole.

As part of our effort in identifying phosphodiesterase (PDE) 4B-preferring inhibitors for the treatment of central nervous system (CNS) disorders, we sought to identify a positron emission tomography (PET) ligand to enable target occupancy measurement in vivo. Through a systematic and cost-effective PET discovery process, involving expression level (B) and biodistribution determination, a PET-specific structure-activity relationship (SAR) effort, and specific binding assessment using a LC-MS/MS "cold tracer" method, we have identified 8 (PF-06445974) as a promising PET lead. Compound 8 has exquisite potency at PDE4B, good selectivity over PDE4D, excellent brain permeability, and a high level of specific binding in the "cold tracer" study. In subsequent non-human primate (NHP) PET imaging studies, [F]8 showed rapid brain uptake and high target specificity, indicating that [F]8 is a promising PDE4B-preferring radioligand for clinical PET imaging.

The Foothills Erratics Train consists of large quartzite blocks of Rocky Mountains origin deposited on the eastern slopes of the Rocky Mountain Foothills in Alberta between ~53.5°N and 49°N. The blocks were deposited in their present locations when the western margin of the Laurentide Ice Sheet (LIS) detached from the local ice masses of the Rocky Mountains, which initiated the opening of the southern end of the ice-free corridor between the Cordilleran Ice Sheet and the LIS. We use 10Be exposure dating to constrain the beginning of this decoupling. Based on a group of 12 samples well-clustered in time, we date the detachment of the western LIS margin from the Rocky Mountain front to ~14.9 ± 0.9 ka. This is ~1000 years later than previously assumed, but a lack of a latitudinal trend in the ages over a distance of ~500 km is consistent with the rapid opening of a long wedge of unglaciated terrain portrayed in existing ice-retreat reconstructions. A later separation of the western LIS margin from the mountain front implies higher ice margin–retreat rates in order to meet the Younger Dryas ice margin position near the boundary of the Canadian Shield ~2000 years later.

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