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P1‐083: Preclinical Pharmacology of Bace Inhibitor CNP520
Author(s) -
Neumann Ulf,
Jacobson Laura Helen,
Perrot Ludovik,
Beltz Karen,
Vogg Barbara,
Brzak Irena,
Tanja Dittmar,
Trappe Vera,
Kolly Carine,
Frieauff Wilfried,
Dubost Valerie,
Jivkov Magali Natacha,
Theil Diethilde,
Staufenbiel Matthias,
Shimshek Derya Robert
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.831
Subject(s) - pharmacology , chemistry , amyloid precursor protein , amyloid precursor protein secretase , in vitro , medicine , alzheimer's disease , disease , biochemistry
neuronal culture assay with an EC50of approximately 250 pM. Following acute oral treatment with 0, 0.3, 1.0, or 3.0 mg/kg LY3202626, dose-dependent reductions in Ab, sAPPb, and C99 were observed in cortex and hippocampus of PDAPPmice. In beagle dog, acute oral dosing of 1.5 mg/kg LY3202626 resulted in lowering of plasma and CSF Ab 1-x by approximately 80% at the nadir; the CSF Ab 1-x was still reduced by approximately 75% at 24 hours post-dosing. Exposure of LY3202626 in plasma and CSF correlated significantly with pharmacodynamic effects upon Ab in both PDAPP mice and beagle dogs. Conclusions:LY3202626 is a potent and selective inhibitor of the BACE1 and BACE2 enzymes. The robust in vivo effects of LY3202626 are consistent with its in vitro potency and exposure in target compartments. These data support further clinical development of LY3202626 for the treatment of AD.