The Potent BACE1 Inhibitor LY2886721 Elicits Robust Central Aβ Pharmacodynamic Responses in Mice, Dogs, and Humans

Abstract

BACE1 is a key protease controlling the formation of amyloid ␤, 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 academiaandindustry.Herein,wereportthenonclinicalandearlyclinicaldevelopmentofLY2886721,aBACE1activesiteinhibitorthatreached 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 ␤ lowering in nonclinical animal models. Similar potent and persistent amyloid ␤ 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.

A digital enzyme-linked immunosorbent assay for ultrasensitive measurement of amyloid-β 1–42 peptide in human plasma with utility for studies of Alzheimer’s disease therapeutics

“…This Simoa assay was able to accurately quantify Aβ 1–42 in all plasma samples tested, demonstrating its capability to support studies of Aβ-lowering therapeutics for AD. Similar to previous findings, oral administration of LY2886721 produced rapid and sustained reductions in plasma Aβ 1–42 levels [24, 32]. Compared with placebo treatment, reductions of Aβ 1–42 concentrations were measureable within 1 h, and remained relatively unchanged after 6 h, following single oral doses of LY2886721 in study I4O-MC-BACA.…”

“…The aim of this study was to develop and evaluate a Simoa assay for Aβ 1–42 with the same amyloid-β-specific antibodies (3D6 and 21F12) used as reagents in previous studies for measurements in human CSF and plasma following treatment with BACE inhibitors [24, 32, 35]. The analytical sensitivity of existing assays available was only just sufficient to quantify the extremely low plasma levels of Aβ 1–42 resulting from treatment [32], suggesting a need for improved assays to support development of more potent BACE inhibitors in the future.…”

“…Nevertheless, plasma Aβ 1–42 continues to be of great interest as a pharmacodynamic marker of γ-secretase (GS) and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) drug target engagement in studies of candidate therapeutics [20, 21]. For example, monitoring the pharmacodynamic changes in plasma Aβ 1–42 levels can aid in the dose optimization of GS or BACE1 [20–24]. Assays that are sensitive enough to allow accurate and precise quantification of low concentrations of Aβ 1–42 in plasma in clinical trials of candidate Aβ-lowering therapeutics would benefit AD research efforts.…”

BACE inhibition-dependent repair of Alzheimer’s pathophysiology

“…NB-360 inhibits the enzymatic activity of BACE, which is required for the generation of Aβ peptides from APP (12). Indeed, quantification of Aβ revealed a substantial reduction of the Aβ plaque burden ( (9,13).…”

Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents

“…21,22 This new disclosure from Eli Lilly prompted us to replace the pyrimidyl moiety of 18 with a picolinamide. To test this approach, we prepared the 4-des-methyl aminothiazine 20 using the three-component, one-pot reaction of 5-chloro-N-(4-fluoro-3-formylphenyl)picolinamide, 3,5-dimethyl-4-vinylisoxazole and thiourea (scheme not shown).…”