Chronic treatment with a novel γ‐secretase modulator, JNJ‐40418677, inhibits amyloid plaque formation in a mouse model of Alzheimer's disease

Abstract

BACKGROUND AND PURPOSE γ‐Secretase modulators represent a promising therapeutic approach for Alzheimer's disease (AD) because they selectively decrease amyloid β 42 (Aβ42), a particularly neurotoxic Aβ species that accumulates in plaques in the brains of patients with AD. In the present study, we describe the in vitro and in vivo pharmacological properties of a potent novel γ‐secretase modulator, 2‐(S)‐(3,5‐bis(4‐(trifluoromethyl)phenyl)phenyl)‐4‐methylpentanoic acid (JNJ‐40418677). EXPERIMENTAL APPROACH The potency and selectivity of JNJ‐40418677 for Aβ reduction was investigated in human neuroblastoma cells, rat primary neurones and after treatment with single oral doses in non‐transgenic mouse brains. To evaluate the effect of JNJ‐40418677 on plaque formation, Tg2576 mice were treated from 6 until 13 months of age via the diet. KEY RESULTS JNJ‐40418677 selectively reduced Aβ42 secretion in human neuroblastoma cells and rat primary neurones, but it did not inhibit Notch processing or formation of other amyloid precursor protein cleavage products. Oral treatment of non‐transgenic mice with JNJ‐40418677 resulted in an excellent brain penetration of the compound and a dose‐ and time‐dependent decrease of brain Aβ42 levels. Chronic treatment of Tg2576 mice with JNJ‐40418677 reduced brain Aβ levels, the area occupied by plaques and plaque number in a dose‐dependent manner compared with transgenic vehicle‐treated mice. CONCLUSIONS AND IMPLICATIONS JNJ‐40418677 selectively decreased Aβ42 production, showed an excellent brain penetration after oral administration in mice and lowered brain Aβ burden in Tg2576 mice after chronic treatment. JNJ‐40418677 therefore warrants further investigation as a potentially effective disease‐modifying therapy for AD.

Modulation of γ-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice

“…We also showed that EVP-0015962 treatment of H4-APP 751 cells did not cause the accumulation of APP α- or β-CTFs at concentrations up to 10 μM, whereas the GSI LY-411,575 [16] led to their accumulation at a concentration as low as 1 nM (Figure 4B). Full length APP was not altered by treatment with either EVP-0015962 or LY-411,575, consistent with published findings [27,30,33,34]. …”

“…Chronic treatment of Tg2576 mice with other GSMs has demonstrated reductions in amyloid deposition [25-27]. Similarly, the histological analyses of the chronically treated Tg2576 mice demonstrated reductions in percent area and number of amyloid plaques in the neocortex and hippocampus.…”

Potent benzoazepinone γ-secretase modulators with improved bioavailability

“…The first GSM chemotypes were derived from NSAID carboxylic acids, with examples being EVP-0015962 5 which has completed phase II, as well as JNJ-40418677 6 and BIIB042. 7 Merck has developed piperidine carboxylic acids, such as GSM-1 8 and GSM-2, 9 which recently have been well-characterized.…”

γ-Secretase Modulator (GSM) Photoaffinity Probes Reveal Distinct Allosteric Binding Sites on Presenilin

“…These compounds were important chemical tools that provided evidence that ␥-secretase could be modulated to reduce the more pathogenic A␤42 species, but that the in vitro potencies are weak (A␤42 IC 50 Ͼ 50 M) and brain penetration is limited. Several next generation NSAID-like GSMs with improved in vitro potency and brain penetration have recently been reported, including GSM-1, GSM-10h, and JNJ-40418677 (17)(18)(19). The non-NSAID-derived imidazole GSMs have a slightly different profile in that they lower the production of A␤42 and A␤40 while increasing the levels of A␤38 and A␤37 to differing degrees.…”