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Publication Abstract from PubMed

BACE1 is a key protease controlling the formation of amyloid beta, 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 beta lowering in nonclinical animal models. Similar potent and persistent amyloid beta 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.

The Potent BACE1 Inhibitor LY2886721 Elicits Robust Central Abeta Pharmacodynamic Responses in Mice, Dogs, and Humans.,May PC, Willis BA, Lowe SL, Dean RA, Monk SA, Cocke PJ, Audia JE, Boggs LN, Borders AR, Brier RA, Calligaro DO, Day TA, Ereshefsky L, Erickson JA, Gevorkyan H, Gonzales CR, James DE, Jhee SS, Komjathy SF, Li L, Lindstrom TD, Mathes BM, Martenyi F, Sheehan SM, Stout SL, Timm DE, Vaught GM, Watson BM, Winneroski LL, Yang Z, Mergott DJ J Neurosci. 2015 Jan 21;35(3):1199-210. doi: 10.1523/JNEUROSCI.4129-14.2015. PMID:25609634^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.