Background BACE1 is a key protease targeting the amyloid processing pathways in AD. Previously we published on LY2811376, the first small molecule BACE1 inhibitor reported to provide robust CSF Abeta changes in healthy subjects. LY2811376 progressed to clinical trials but was terminated due to non-clinical tox findings. Here we report the preclinical pharmacology of LY2886721, a new BACE1 inhibitor that is in clinical development for early AD. Methods Enzyme assays were conducted with recombinant enzymes using a FRET platform. Cell based assays were conducted with either a HEK293Swe cell line or primary neuronal cultures prepared from PDAPP mice. D ose response and time course studies were conducted in young PDAPP transgenic mice with brain collected at various times after oral gavage and extracts analyzed by ELISA for relevant PD biomarkers including Abeta, C99 and sAPPbeta. Plasma and CSF PK/PD studies were conducted in beagle dogs using a multi-week paradigm which involved establishing vehicle-treated baseline CSF Abeta values for within dog comparison to subsequent CSF samples taken from LY-treated dogs. Results LY2886721 inhibited recombinant hBACE1 with an IC50 of 20.3 nM. In cellular assays, LY2886721 inhibited Abeta with an IC50 of 18.7 nM and 10.7 nM, HEK293Swe and PDAPP
Alzheimer's and Dementia – Elsevier
Published: Jul 1, 2012
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