2. Academic Validation
  3. The potent BACE1 inhibitor LY2886721 elicits robust central Aβ pharmacodynamic responses in mice, dogs, and humans

The potent BACE1 inhibitor LY2886721 elicits robust central Aβ pharmacodynamic responses in mice, dogs, and humans

  • J Neurosci. 2015 Jan 21;35(3):1199-210. doi: 10.1523/JNEUROSCI.4129-14.2015.
Patrick C May 1,  Brian A Willis 1,  Stephen L Lowe 2,  Robert A Dean 1,  Scott A Monk 1,  Patrick J Cocke 1,  James E Audia 1,  Leonard N Boggs 1,  Anthony R Borders 1,  Richard A Brier 1,  David O Calligaro 1,  Theresa A Day 1,  Larry Ereshefsky 3,  Jon A Erickson 1,  Hykop Gevorkyan 4,  Celedon R Gonzales 1,  Douglas E James 1,  Stanford S Jhee 3,  Steven F Komjathy 1,  Linglin Li 1,  Terry D Lindstrom 1,  Brian M Mathes 1,  Ferenc Martényi 1,  Scott M Sheehan 1,  Stephanie L Stout 1,  David E Timm 1,  Grant M Vaught 1,  Brian M Watson 1,  Leonard L Winneroski 1,  Zhixiang Yang 1,  Dustin J Mergott 5
Affiliations

Affiliations

  • 1 Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
  • 2 National University of Singapore Centre for Clinical Pharmacology, Singapore 117597, Singapore.
  • 3 PAREXEL International, Glendale, California 91206, and.
  • 4 California Clinical Trials Medical Group, Inc., Glendale, California 91206.
  • 5 Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, [email protected].
PMID: 25609634 DOI: 10.1523/JNEUROSCI.4129-14.2015
Abstract

BACE1 is a key protease controlling the formation of amyloid β, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid β lowering in nonclinical animal models. Similar potent and persistent amyloid β lowering was observed in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD.

Keywords

Alzheimer's disease; BACE1; amyloid beta; clinical trial; nonclinical animal model.

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