2018
DOI: 10.1021/acsmedchemlett.8b00099
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Design, Synthesis, and Blood–Brain Barrier Transport Study of Pyrilamine Derivatives as Histone Deacetylase Inhibitors

Abstract: We designed and synthesized a pyrilamine derivative 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 is a substrate of PYSOCA. Thus, our findings suggest that the hybrid method of HDAC inhibitor and substrate of PYS… Show more

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Cited by 24 publications
(14 citation statements)
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References 42 publications
(59 reference statements)
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“…1 H-NMR (400 MHz, CDCl 3 ) δ 7.42 (dd, J = 1.8, 0.8 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.14–7.07 (m, 2H), 6.55 (dd, J = 3.4, 0.8 Hz, 1H), 6.44 (dd, J = 3.4, 1.8 Hz, 1H), 6.26 (s, 1H), 3.77 (s, 2H), 1.52 (s, 9H); 13 C-NMR (101 MHz, CDCl 3 ) δ 153.90, 153.86, 141.88, 139.86, 128.80, 124.70, 124.46, 115.71, 113.03, 111.71, 104.73, 80.80, 28.47 (in accordance with literature [ 63 ]).…”
Section: Methodssupporting
confidence: 85%
See 1 more Smart Citation
“…1 H-NMR (400 MHz, CDCl 3 ) δ 7.42 (dd, J = 1.8, 0.8 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.14–7.07 (m, 2H), 6.55 (dd, J = 3.4, 0.8 Hz, 1H), 6.44 (dd, J = 3.4, 1.8 Hz, 1H), 6.26 (s, 1H), 3.77 (s, 2H), 1.52 (s, 9H); 13 C-NMR (101 MHz, CDCl 3 ) δ 153.90, 153.86, 141.88, 139.86, 128.80, 124.70, 124.46, 115.71, 113.03, 111.71, 104.73, 80.80, 28.47 (in accordance with literature [ 63 ]).…”
Section: Methodssupporting
confidence: 85%
“…The reduction in compound 2d (1.78 g, 5.85 mmol) was performed according to the general procedure A2b in 42 mL 1,4-dioxane/H 2 O (5:1, v/v) to give after purification by flash chromatography (silica, gradient PE/EA: 4:1 → 2:1 → 1:1) compound 3d (1.34 g, 83%) as white-beige solid. [63]).…”
Section: Synthesis Of Tert-butyl [2-amino-4-(furan-2-yl)phenyl]carbam...mentioning
confidence: 99%
“…Hiranaka et al 142 described the design, synthesis and pharmacokinetic evaluations of compound 7 as a selective class I HDACi that targets pyrilamine‐sensitive proton‐coupled organic cation antiporter (PYSOCA). They adopted a hybrid strategy based on linking benzamide‐type HDACis with substrates of PYSOCA (Figure 6).…”
Section: Case Studies Of Hdac Inhibition Associated With Ndsmentioning
confidence: 99%
“…Both compounds 7 and CI‐994 ( 3 ) increased the AcH3K9 levels in HeLa S3 cells at 10 µM; however, 7 showed slow kinetics to promote AcH3K9, indicating a time‐dependent inhibition of HDACs in vitro. Compound 7 was shown to be absorbed via PYSOCA antiporter in a manner dependent on an external H + ‐gradient 142 . The BBB permeability of compound 7 and CI‐994 ( 3 ) was also determined, and it was 3.3‐fold greater for compound 7 than for CI‐994 ( 3 ) (compound 7 = 42.4 µL/min/g; CI‐994 ( 3 ) = 12.7 µL/min/g), 142 showing the promising profile of compound 7 for the treatment of NDs.…”
Section: Case Studies Of Hdac Inhibition Associated With Ndsmentioning
confidence: 99%
“…We previously investigated drug delivery utilizing the H þ /OC antiporter, and designed a hybrid compound composed of pyrilamine and CI-994, a histone deacetylase inhibitor. 16 This compound was recognized by the H þ /OC antiporter and showed increased BBB permeability compared to CI-994 itself, which has a very low BBB permeability. Wang et al also reported that the BBB permeability of naproxen was increased by conjugation with compounds having a tertiary amine moiety.…”
Section: Introductionmentioning
confidence: 99%