BACE1 (β-site amyloid precursor protein cleaving enzyme 1) inhibitors are known as one of the promising disease-modifying agent in several clinical trials for the treatment of Alzheimer’s disease. JNJ-54861911 has been originally discovered at Shionogi Pharmaceutical Research Center (Osaka, Japan) in 2008 as a potent orally active small molecule BACE1 inhibitor, which is being developed by Janssen Research & Development, LLC, in New Jersey. JNJ-54861911 showed IC50 of 9.8 nM in human BACE1 enzyme assay with high selectivity towards Cathepsin D (IC50: &gt;25000 nM). JNJ-54861911 has well balanced membrane permeable characteristics showing higher IC50 value (Aβ40 1.1 nM) in cell based Aβ production assay compared to enzyme based assay. The compound is orally active with good brain penetration and low P-gp substrate characteristic, which reflects in vivo Aβ reduction (in brain, in CSF) in multi species animals such as rat, monkey, and dog. Here, we report and disclose as first time, the design concept, chemical synthesis, and structure including X-ray crystal structure analysis of this compound.

Discovery and synthesis of JNJ-54861911, a novel orally active BACE1 inhibitor

255th National Meeting (2018)

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