“…CNS drugs must be able to efficiently cross the blood–brain barrier (BBB). However, cell permeability and brain penetration constitute a major hurdle in the development of some classes of anti-Alzheimer drugs, particularly in BACE-1 inhibitors and in Aβ and tau aggregation inhibitors. ,,, Moreover, compounds designed by combination of two pharmacophoric moieties, such as the novel rhein–huprine hybrids, usually have molecular weights over 500, which might challenge their ability to cross cell membranes. , However, different families of anti-Alzheimer hybrid compounds with molecular weights over 500 have shown good oral availability and/or brain permeability in ex vivo and in vivo studies in mice. ,,, Even though the potential of a CNS drug to enter into the brain also depends on a low P-glycoprotein efflux liability, , a good brain permeability is a necessary requirement. In this work, the brain permeability of the novel rhein–huprine hybrids has been predicted through the widely known parallel artificial membrane permeation assay (PAMPA-BBB) .…”