The Novel γ Secretase Inhibitor N-[cis-4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) Reduces Amyloid Plaque Deposition without Evidence of Notch-Related Pathology in the Tg2576 Mouse

Abstract

There is a substantial body of evidence indicating that ␤-amyloid peptides (A␤) are critical factors in the onset and development of Alzheimer's disease (AD). One strategy for combating AD is to reduce or eliminate the production of A␤ through inhibition of the ␥-secretase enzyme, which cleaves A␤ from the amyloid precursor protein (APP). We demonstrate here that chronic treatment for 3 months with 3 mg/kg of the potent, orally bioavailable and brain-penetrant ␥-secretase inhibitor N- [cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) attenuates the appearance of amyloid plaques in the Tg2576 mouse. These reductions in plaques were also accompanied by a decrease in the level of reactive gliosis. The morphometric and histological measures agreed with biochemical analysis of A␤(40) and A␤(42) in the cortex.

Alzheimer's Disease: Presenilin 2-Sparing γ-Secretase Inhibition Is a Tolerable Aβ Peptide-Lowering Strategy

“…In these cells, we found that MRK-560 inhibited all A␤ species analyzed with similar potency, and displayed approximately sixfold selectivity for A␤42 over NICD formation (Fig. 1A), which is in line with a previous report (Best et al, 2007). Next we addressed (BD8)).…”

“…In the context of AD, it is of particular interest that PS1 seems to catalyze the vast majority of CNS A␤ production (De Strooper et al, 1998;Borgegard et al, 2011) and that certain GSIs of the sulfonamide class appear to exhibit a preference for PS1 over PS2 ␥-secretase activities (Zhao et al, 2008;Borgegard et al, 2011), supporting the notion that development of ␥-secretase subcomplex selective GSIs may be feasible. In line with this, the sulfonamide GSI, MRK-560, inhibits A␤ production in an efficacious manner and reduces neural plaque formation without producing the Notchrelated off target effects observed in chronic studies in mice (Best et al, 2007). The mechanism by which Notch signaling is spared using MRK-560 has, however, not been unraveled, but is important to elucidate, as such information may guide development of the next generation GSIs.…”

“…The preference of MRK-560 for PS1-containing ␥-secretase prompted us to explore whether the spared Notch signaling observed in vivo (Best et al, 2007) was a consequence of MRK-560 having an altered distribution in brain or plasma that precluded MRK-560 from reaching peripheral organs as efficiently as reaching the brain. To address this in vivo, WT and PS2-deficient mice were subjected to MRK-560 over 4 consecutive days and levels of MRK-560 were analyzed in plasma and brain 3 h after final administration.…”

1-(3′,4′-Dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-cyclopropanecarboxylic Acid (CHF5074), a Novel γ-Secretase Modulator, Reduces Brain β-Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease without Causing Peripheral Toxicity

“…Another study in 10-month-old Tg2576 mice receiving ibuprofen in the diet for 6 months (375 ppm) produced also similar results (Lim et al, 2000). Comparable effects were also recently described in 15-month-old Tg2576 mice after chronic treatment with the ␥-secretase inhibitor MRK-560 (3 mg/kg/day for 3 months; Best et al, 2007).…”

“…In addition, ␥-secretase inhibitors have been associated to alteration of lymphopoiesis (Wong et al, 2004) and atrophy of the thymus (Hadland et al, 2001). Toxicity of the ␥-secretase inhibitors may be linked to the specific chemical structure, since it has been shown that MRK-560, a potent APP and Notch cleavage inhibitor (IC 50 values ϭ 4.32 and 3.44 nM, respectively), administered for 3 months to aged Tg2576 mice significantly reduced brain A␤ pathology without causing histopathological changes in the ileum, spleen, or thymus (Best et al, 2007). Our present studies in HEK293swe cells indicated that CHF5074 concentrations inhibiting APP processing (5 M) do not affect Notch processing.…”