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Design, Synthesis, and Blood–Brain Barrier Transport Study of Pyrilamine Derivatives as Histone Deacetylase Inhibitors

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journal contribution
posted on 23.08.2018, 00:00 by Seiya Hiranaka, Yuma Tega, Kei Higuchi, Toshiki Kurosawa, Yoshiharu Deguchi, Mayumi Arata, Akihiro Ito, Minoru Yoshida, Yasuo Nagaoka, Takaaki Sumiyoshi
We designed and synthesized a pyrilamine derivative 1 as a selective class I HDAC inhibitor that targets pyrilamine-sensitive proton-coupled organic cation antiporter (PYSOCA) at the blood–brain barrier (BBB). Introduction of pyrilamine moiety to benzamide type HDAC inhibitors kept selective class I HDAC inhibitory activity and increased BBB permeability. Our BBB transport study showed that compound 1 is a substrate of PYSOCA. Thus, our findings suggest that the hybrid method of HDAC inhibitor and substrate of PYSOCA such as pyrilamine is useful for development of HDAC inhibitors with increased BBB permeability.