Orally bioavailable and brain-penetrant pyridazine and pyridine-derived γ-secretase modulators reduced amyloidogenic Aβ peptides in vivo

γ-Secretase Modulators

“…Efficacy has been demonstrated in a range of studies. These results are in contrast to the in vitro profile where the compound shows an increase in Ab 38 . In a time course study in non-transgenic mice at 30 mg/kg p.o.…”

“…Both of these compounds displayed potent in vitro activity (Ab 42 IC 50 ¼ 71 and 28 nM, respectively). This compound was more active and decreased brain Ab 42 by 62% and gave a 66% increase in brain Ab 38 . This gave a 22% decrease in brain Ab 42 and a 17% increase in brain Ab 38 levels.…”

“…Using the same CNS penetration study design as for compound (17), (18) showed good concentration in blood and brain, 5 and 8.7 mM, respectively, with an apparent increase in CNS penetration, (Br:Bl ¼ 1.74 cf (17) Br:Bl ¼ 0.49). Further characterisation of (17) and (18) (also known respectively as GSM-C and GSM-D) has recently been published [38]. The in vitro activity was confirmed in rat primary cortical neurons (48 h incubation) where (17) (17) and (18), respectively.…”

“…Adverse events have been related to the possible non-selective nature of these inhibitors and this has focussed efforts on the identification of g-secretase modulators (GSMs) which may offer selective targeting of amyloid cleavage over other substrates, such as Notch. In addition to this, the levels of shorter amyloid species such as Ab 37 and Ab 38 are increased, which again forces questions about the functional importance and potential adverse consequences due to increased levels of these lesser studied peptides. In addition, various modes of action are possible, such as selective lowering of Ab 42 , or simultaneous lowering of Ab 42 and Ab 40 , which can force scientists to make a strategic decision about which may be the main pathogens.…”