7 research outputs found
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Pharmacological and Toxicological Properties of the Potent Oral γ-Secretase Modulator BPN-15606.
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
Recommended from our members
Pharmacological and Toxicological Properties of the Potent Oral γ-Secretase Modulator BPN-15606.
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
Spontaneous and Thiazolidinedione-Induced B6C3F1 Mouse Hemangiosarcomas Exhibit Low ras Oncogene Mutation Frequencies
Stardust-NExT, Deep Impact, and the accelerating spin of 9P/Tempel 1
The evolution of the spin rate of Comet 9P/Tempel 1 through two perihelion passages (in 2000 and 2005) is determined from 1922 Earth-based observations taken over a period of 13. year as part of a World-Wide observing campaign and from 2888 observations taken over a period of 50 days from the Deep Impact spacecraft. We determine the following sidereal spin rates (periods): 209.023 ± 0.025°/dy (41.335 ± 0.005. h) prior to the 2000 perihelion passage, 210.448 ± 0.016°/dy (41.055 ± 0.003. h) for the interval between the 2000 and 2005 perihelion passages, 211.856 ± 0.030°/dy (40.783 ± 0.006. h) from Deep Impact photometry just prior to the 2005 perihelion passage, and 211.625 ± 0.012°/dy (40.827 ± 0.002. h) in the interval 2006-2010 following the 2005 perihelion passage. The period decreased by 16.8 ± 0.3. min during the 2000 passage and by 13.7 ± 0.2. min during the 2005 passage suggesting a secular decrease in the net torque. The change in spin rate is asymmetric with respect to perihelion with the maximum net torque being applied on approach to perihelion. The Deep Impact data alone show that the spin rate was increasing at a rate of 0.024 ± 0.003°/dy/dy at JD2453530.60510 (i.e., 25.134 dy before impact), which provides independent confirmation of the change seen in the Earth-based observations.The rotational phase of the nucleus at times before and after each perihelion and at the Deep Impact encounter is estimated based on the Thomas et al. (Thomas et al. [2007]. Icarus 187, 4-15) pole and longitude system. The possibility of a 180° error in the rotational phase is assessed and found to be significant. Analytical and physical modeling of the behavior of the spin rate through of each perihelion is presented and used as a basis to predict the rotational state of the nucleus at the time of the nominal (i.e., prior to February 2010) Stardust-NExT encounter on 2011 February 14 at 20:42.We find that a net torque in the range of 0.3-2.5×107kgm2s-2 acts on the nucleus during perihelion passage. The spin rate initially slows down on approach to perihelion and then passes through a minimum. It then accelerates rapidly as it passes through perihelion eventually reaching a maximum post-perihelion. It then decreases to a stable value as the nucleus moves away from the Sun. We find that the pole direction is unlikely to precess by more than ~1° per perihelion passage. The trend of the period with time and the fact that the modeled peak torque occurs before perihelion are in agreement with published accounts of trends in water production rate and suggests that widespread H2O out-gassing from the surface is largely responsible for the observed spin-up. © 2011 Elsevier Inc