title: Modulation of γ-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice.
abstract: BACKGROUND
  A hallmark of Alzheimer's disease is the presence of senile plaques in human brain primarily containing the amyloid peptides Aβ42 and Aβ40. Many drug discovery efforts have focused on decreasing the production of Aβ42 through γ-secretase inhibition. However, identification of γ-secretase inhibitors has also uncovered mechanism-based side effects. One approach to circumvent these side effects has been modulation of γ-secretase to shift Aβ production to favor shorter, less amyloidogenic peptides than Aβ42, without affecting the overall cleavage efficiency of the enzyme. This approach, frequently called γ-secretase modulation, appears more promising and has lead to the development of new therapeutic candidates for disease modification in Alzheimer's disease.
  
  
  RESULTS
  Here we describe EVP-0015962, a novel small molecule γ-secretase modulator. EVP-0015962 decreased Aβ42 in H4 cells (IC50 = 67 nM) and increased the shorter Aβ38 by 1.7 fold at the IC50 for lowering of Aβ42. AβTotal, as well as other carboxyl-terminal fragments of amyloid precursor protein, were not changed. EVP-0015962 did not cause the accumulation of other γ-secretase substrates, such as the Notch and ephrin A4 receptors, whereas a γ-secretase inhibitor reduced processing of both. A single oral dose of EVP-0015962 (30 mg/kg) decreased Aβ42 and did not alter AβTotal peptide levels in a dose-dependent manner in Tg2576 mouse brain at an age when overt Aβ deposition was not present. In Tg2576 mice, chronic treatment with EVP-0015962 (20 or 60 mg/kg/day in a food formulation) reduced Aβ aggregates, amyloid plaques, inflammatory markers, and cognitive deficits.
  
  
  CONCLUSIONS
  EVP-0015962 is orally bioavailable, detected in brain, and a potent, selective γ-secretase modulator in vitro and in vivo. Chronic treatment with EVP-0015962 was well tolerated in mice and lowered the production of Aβ42, attenuated memory deficits, and reduced Aβ plaque formation and inflammation in Tg2576 transgenic animals. In summary, these data suggest that γ-secretase modulation with EVP-0015962 represents a viable therapeutic alternative for disease modification in Alzheimer's disease.
authors.affiliation: EnVivo Pharmaceuticals, Inc, 500 Arsenal Street, Watertown, MA 02472, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Rogers
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Felsenstein
authors.forename: Lori
authors.initials: L
authors.lastname: Hrdlicka
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Tu
authors.forename: Faris
authors.initials: F
authors.lastname: Albayya
authors.forename: Winnie
authors.initials: W
authors.lastname: Lee
authors.forename: Sarah
authors.initials: S
authors.lastname: Hopp
authors.forename: Mary-Jo
authors.initials: MJ
authors.lastname: Miller
authors.forename: Darcie
authors.initials: D
authors.lastname: Spaulding
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Yang
authors.forename: Hilliary
authors.initials: H
authors.lastname: Hodgdon
authors.forename: Scott
authors.initials: S
authors.lastname: Nolan
authors.forename: Melody
authors.initials: M
authors.lastname: Wen
authors.forename: Don
authors.initials: D
authors.lastname: Costa
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Blain
authors.forename: Emily
authors.initials: E
authors.lastname: Freeman
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.forename: Veerle
authors.initials: V
authors.lastname: Vulsteke
authors.forename: Louise
authors.initials: L
authors.lastname: Scrocchi
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.forename: Erik
authors.initials: E
authors.lastname: Portelius
authors.forename: Birgit
authors.initials: B
authors.lastname: Hutter-Paier
authors.forename: Daniel
authors.initials: D
authors.lastname: Havas
authors.forename: Michael
authors.initials: M
authors.lastname: Ahlijanian
authors.forename: Dorothy
authors.initials: D
authors.lastname: Flood
authors.forename: Liza
authors.initials: L
authors.lastname: Leventhal
authors.forename: Gideon
authors.initials: G
authors.lastname: Shapiro
authors.forename: Holger
authors.initials: H
authors.lastname: Patzke
authors.forename: Richard
authors.initials: R
authors.lastname: Chesworth
authors.forename: Gerhard
authors.initials: G
authors.lastname: Koenig
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases / Q000187:drug effects* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010666:Phenylpropionates / Q000494:pharmacology*; D011422:Propionates / Q000494:pharmacology*; D014162:Transfection
chemical_list: C582516:2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid; D016229:Amyloid beta-Peptides; D001713:Biphenyl Compounds; D010666:Phenylpropionates; D011422:Propionates; D053829:Amyloid Precursor Protein Secretases