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.
Yuji KoriyamaAkihiro HoriHisanori ItoShuji YonezawaYoshiyasu BabaNorihiko TanimotoTatsuhiko UenoShiho YamamotoTakahiko YamamotoNaoya AsadaKenji MorimotoShunsuke EinaruKatsunori SakaiTakushi KanazuAkihiro MatsudaYoshitaka YamaguchiTakuya OgumaMaarten TimmersLuc TritsmansKen-Ichi KusakabeAkira KatoGaku SakaguchiPublished in: Journal of medicinal chemistry (2021)
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.
Keyphrases
- clinical trial
- phase ii
- study protocol
- end stage renal disease
- phase iii
- endothelial cells
- ejection fraction
- newly diagnosed
- chronic kidney disease
- binding protein
- small molecule
- amino acid
- randomized controlled trial
- protein protein
- double blind
- cell therapy
- stem cells
- prognostic factors
- transcription factor
- mild cognitive impairment
- climate change
- single cell
- liver injury