Design, synthesis and biological evaluation of brain penetrant benzazepine-based histone deacetylase 6 inhibitors for alleviating stroke-induced brain infarction

Guo, Zheng; Zixue, Zhang; Zhang, Yi; Wang, Guan; Huang, Zhensheng; Zhang, Qinwei; Li, Jianqi

doi:10.1016/j.ejmech.2021.113383

Cited by 17 publications

(12 citation statements)

References 41 publications

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“…For example, benzazepine is a common fragment found in many CNS drugs, such as diazepam, galantamine, and lorcaserin (Figure 11). 101 The following are excellent investigations of adjusting molecular rigidity to affect BBB permeability.…”

Section: Strategies For Enhancing the Bbbmentioning

confidence: 99%

Strategies for Structural Modification of Small Molecules to Improve Blood–Brain Barrier Penetration: A Recent Perspective

et al. 2021

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In the development of central nervous system (CNS) drugs, the blood–brain barrier (BBB) restricts many drugs from entering the brain to exert therapeutic effects. Although many novel delivery methods of large molecule drugs have been designed to assist transport, small molecule drugs account for the vast majority of the CNS drugs used clinically. From this perspective, we review studies from the past five years that have sought to modify small molecules to increase brain exposure. Medicinal chemists make it easier for small molecules to cross the BBB by improving diffusion, reducing efflux, and activating carrier transporters. On the basis of their excellent work, we summarize strategies for structural modification of small molecules to improve BBB penetration. These strategies are expected to provide a reference for the future development of small molecule CNS drugs.

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Section: Strategies For Enhancing the Bbbmentioning

confidence: 99%

Strategies for Structural Modification of Small Molecules to Improve Blood–Brain Barrier Penetration: A Recent Perspective

et al. 2021

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“…After tail vein injection of a 1.5 mg/kg dose, the concentrations of the compounds in the brain and plasma were measured after 5 min and 60 min of administration, and the brain/plasma (B/P) ratio was calculated. The samples of plasma and brain tissue were prepared as previously reported 47 . An established LC-MS/MS method was used for determining the concentration of representative compounds in plasma and brain tissue.…”

Section: Methodsmentioning

confidence: 99%

Design and synthesis of benzodiazepines as brain penetrating PARP-1 inhibitors

Gou

Hong

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…In vitro HDAC6 and HDAC1 inhibition assays were conducted by Sundia Corporation. The detailed method was described in our previous article (Guo et al, 2021). In brief, compounds were tested in 7-dose IC 50 mode in duplicate from 8 μM to dilute in fourfold.…”

Section: In Vitro Enzyme Inhibition Assaymentioning

confidence: 99%

“…The detailed method was described in our previous article (Guo et al, 2021). In brief, all the cells treated with various concentration compounds were collected and resuspended.…”

Section: Western Blottingmentioning

confidence: 99%

Synthesis and structure‐activity relationship of thiol‐based histone deacetylase 6 inhibitors

et al. 2022

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Selective histone deacetylase 6 (HDAC6) inhibitors are safe and well‐tolerated with less off‐target effect. However, most available HDAC6 inhibitors contain hydroxamate as a zinc‐binding group (ZBG), and their unfavorable pharmacokinetic properties along with potential genotoxicity limited wide application in diverse diseases. Therefore, we designed and synthesized a series of selective HDAC6 inhibitors utilizing thiol as the ZBG and discussed their structure‐activity relationship based on molecular docking. In particular, compound 21, obtained by constantly step‐by‐step simplification and evolution based on Ricolinostat, a specific HDAC6 inhibitor in Phase II, unexpectedly showed high selectivity (29‐fold) and moderate potency (73 nM). Utilizing pyrimidine as a linker in thiol‐based HDAC6 inhibitors produces an utterly novel structure, which might display different pharmacokinetic properties and genotoxicity.

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Design, synthesis and biological evaluation of brain penetrant benzazepine-based histone deacetylase 6 inhibitors for alleviating stroke-induced brain infarction

Cited by 17 publications

References 41 publications

Strategies for Structural Modification of Small Molecules to Improve Blood–Brain Barrier Penetration: A Recent Perspective

Strategies for Structural Modification of Small Molecules to Improve Blood–Brain Barrier Penetration: A Recent Perspective

Design and synthesis of benzodiazepines as brain penetrating PARP-1 inhibitors

Synthesis and structure‐activity relationship of thiol‐based histone deacetylase 6 inhibitors

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