The evolution of amidine-based brain penetrant BACE1 inhibitors

Bioorg Med Chem Lett. 2014 May 1;24(9):2033-45. doi: 10.1016/j.bmcl.2014.03.025.

Daniel Oehlrich ¹, Hana Prokopcova ², Harrie J M Gijsen ²

Affiliations

1 Neuroscience Medicinal Chemistry, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium. Electronic address: doehlric@its.jnj.com.
2 Neuroscience Medicinal Chemistry, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.

PMID: 24704031 DOI: 10.1016/j.bmcl.2014.03.025

Abstract

Beta site amyloid precursor protein cleaving Enzyme 1 (BACE1) inhibitors hold great potential as disease modifying anti-Alzheimer's drugs. This digest provides an overview of the amidine containing class of BACE1 inhibitors, of which multiple examples are now progressing through clinical trials. The various structural modifications highlight the struggle to combine potency with the optimal properties for a brain penetrant BACE1 Inhibitor, and illustrate the crowded competitive landscape. This overview concludes with a summary of potential issues including substrate and target selectivity and a synopsis of the status of the current and past clinical assets.

Keywords

Alzheimer’s; Amyloid; BACE; BACE1; Inhibitor.

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