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. 2018 Aug 23;9(9):884-888.
doi: 10.1021/acsmedchemlett.8b00099. eCollection 2018 Sep 13.

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

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

Seiya Hiranaka et al. ACS Med Chem Lett. .
Free PMC article

Abstract

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.

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Hybrid design strategy for compound 1.
Figure 2
Figure 2
Time-courses of uptake of (A) compound 1 and (B) CI-994 by hCMEC/D3 cells. Uptake was measured at 37 °C (open circles) or 4 °C (closed squares) for the indicated times. Each point represents the mean ± SE (n = 4). Where the SE is not shown, it is smaller than the symbol. Uptake of 1 and CI-994 by hCMEC/D3 cells increased linearly (black lines) for at least 2 and 1 min, respectively. *p < 0.01, significantly different from the uptake at 4 °C at the corresponding time. (C) Concentration dependency of the uptake of compound 1 by hCMEC/D3 cells. The concentration dependency of the uptake of compound 1 was examined at 37 °C for 2 min. Kinetic parameters obtained from eq 1 (see Supporting Information) were Km 326 ± 72 μM and Vmax 5.17 ± 0.86 nmol/mg protein/min. The solid line was calculated according to eq 1 with these parameters. Each point represents the mean ± SE (n = 4). Where the SE is not shown, it is smaller than the symbol. (D), (E) Dependency of the uptake of compound 1 by hCMEC/D3 cells on metabolic energy (D) and intracellular pH (E). (D) hCMEC/D3 cells were pretreated with NaN3 (0.1%) for 20 min to deplete cellular ATP, and uptake of compound 1 was measured at 37 °C for 2 min. (E) hCMEC/D3 cells were pretreated with transport buffer in the absence (Control and Acute) or presence (Pre) of 30 mM NH4Cl, and then uptake of compound 1 was measured in the absence (Control and Pre) or presence (Acute) of 30 mM NH4Cl at 37 °C for 1 min. Each column represents the mean ± SE (n = 4). *p < 0.01, significantly different from control.
Figure 3
Figure 3
Inhibition by diphenhydramine of the uptake of compound 1 into hCMEC/D3 cells. Uptake of compound 1 at various concentrations was measured at 37 °C for 2 min in the absence (open circles) or presence (closed circles) of diphenhydramine (100 μM). Where the SE is not shown, it is smaller than the symbol. Data were subjected to Michaelis–Menten plot (A) and Lineweaver–Burk plot (B) analysis. Kinetic parameters were obtained by nonlinear least-squares regression according to eqs 1 and 2 (see Supporting Information). The straight lines were drawn using the kinetic parameters obtained. Each point shows the mean ± SE (n = 4).
Figure 4
Figure 4
BBB permeability of compound 1 and CI-994 across the rat BBB. The right cerebral hemisphere of the rat was perfused with buffer containing compound 1 or CI-994 (20 μM) at a rate 4.9 mL/min for 1 min. Each column represents the mean ± SE (n = 3). *p < 0.01, significantly different from the PSBBB of CI-994.
Scheme 1
Scheme 1. Synthesis of the Hybrid Compound 1
Reagents and conditions: (a) pyridine, DMSO, 110 °C, 4.5 h, microwave, 61%; (b) TFA, 0.5 h, 90%.

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