Discovery of Atabecestat (JNJ-54861911): A Thiazine-Based β-Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor Advanced to the Phase 2b/3 EARLY Clinical Trial

Abstract

Accumulation of amyloid β peptides (Aβ) is thought to be one of the causal factors of Alzheimer's disease (AD). The aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting protease for Aβ production, and therefore, BACE1 inhibition is a promising therapeutic approach for the treatment of AD. Starting with a dihydro-1,3-thiazine-based lead, Compound J, we discovered atabecestat 1 (JNJ-54861911) as a centrally efficacious BACE1 inhibitor that was advanced into the EARLY Phase 2b/3 clinical trial for the treatment of preclinical AD patients. Compound 1 demonstrated robust and dose-dependent Aβ reduction and showed sufficient safety margins in preclinical models. The potential of reactive metabolite formation was evaluated in a covalent binding study to assess its irreversible binding to human hepatocytes. Unfortunately, the EARLY trial was discontinued due to significant elevation of liver enzymes, and subsequent analysis of the clinical outcomes showed dose-related cognitive worsening.

Mouse Models of Alzheimer’s Disease

“…BACE1, which is responsible for the N-terminal processing of Aβ, has been investigated as a therapeutic target molecule. Various BACE1 inhibitors, such as verubecestat, umibecestat, and atabecestat have been developed, and their efficacy and pharmacodynamics have been investigated in animal models (Kennedy et al, 2016 ; Neumann et al, 2018 ; Koriyama et al, 2021 ). However, none of them have shown therapeutic effects in clinical trials (Egan et al, 2018 , 2019 ; Novak et al, 2020 ).…”

Strategies for Structural Modification of Small Molecules to Improve Blood–Brain Barrier Penetration: A Recent Perspective

“…On the basis of a rational design of the pK a -decreasing approach, thiazine-based BACE1 inhibitors 39 (JNJ-54861911, Atabecestat) with the most promising profile and decreased ER were advanced to further in vivo studies (Figure 15). 107 In the design of phosphodiesterase 10A (PDE10A) inhibitors, a dual substrate PDE that catalyzes the hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), two similar structures showed extraordinary differences in blood−brain distributions. Investigators assessed TgCPL inhibitors 40 and 41 in vitro to determine whether they were potential substrates of P-gp.…”

Dual Inhibitors of Amyloid-β and Tau Aggregation with Amyloid-β Disaggregating Properties: Extended In Cellulo, In Silico, and Kinetic Studies of Multifunctional Anti-Alzheimer’s Agents

“… 12 , 13 Elenbecestat (E-2609, Eisai), 14 verubecestat (MK-8931, Merck), 15 and atabecestat (JNJ-911, Janssen) 16 reached phase III clinical trials but failed due to lack of clinical efficacy or observed toxicity. 12 , 17 , 18 …”