2011
DOI: 10.1016/j.bmcl.2011.07.020
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Strategies to lower the Pgp efflux liability in a series of potent indole azetidine MCHR1 antagonists

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Cited by 14 publications
(7 citation statements)
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“…65,66 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. 12,40,67,68 Even though the potential of a CNS drug to enter into the brain also depends on a low P-glycoprotein efflux liability, 69,70 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).…”
Section: ■ Results and Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…65,66 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. 12,40,67,68 Even though the potential of a CNS drug to enter into the brain also depends on a low P-glycoprotein efflux liability, 69,70 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).…”
Section: ■ Results and Discussionmentioning
confidence: 99%
“…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) .…”
Section: Resultsmentioning
confidence: 99%
“…Anti-Alzheimer drug candidates, like any other CNS drug, must be able to efficiently enter into the brain, which requires a good ability to cross the blood-brain barrier (BBB) and a low P-glycoprotein efflux liability [25]. The large molecular weight of hybrids 5a-d (>500) might compromise their ability to cross biological membranes, including BBB [26].…”
Section: Blood-brain Barrier Permeation Assaymentioning
confidence: 99%
“…Having explored opportunities to design compounds with improved potency, selectivity, and pharmacokinetics (particularly, in dogs) while mitigating CNS efflux transporter susceptibility and hERG risk in the solvent front, we sought to further refine compound 12 through optimization of the lysine region fragment. Apart from TPSA and HBD count, basicity has been implicated in driving P-gp efflux and CNS penetrance . We surmised that the less basic piperazine may be a suitable piperidine isostere with slightly improved CNS properties despite the net increase in TPSA.…”
Section: Results and Discussionmentioning
confidence: 99%