PZ-2891 is an orally bioavailable, brain penetrant pantothenate kinase (PANK) modulator(hPANK3,IC50:1.3 nM).

PANK1β (human):40.2±4.4 nM (IC50), PANK2 (human):0.7±0.08 nM (IC50), PANK3 (human):1.3±0.2 nM (IC50)

口服PZ-2891能增加小鼠肝脏和大脑中的CoA水平。在脑CoA缺乏的基因敲除小鼠模型中，观察到体重减轻、严重的运动障碍和早期死亡。接受PZ-2891治疗的基因敲除小鼠体重增加，运动活性和寿命得到改善，从而确认了pantazines作为治疗PKAN的新型疗法。

C57Bl6/J mice (8-week-old) ?pantothenic acid-supplemented diet (1000 ppm) for 2 weeks prior to the experiment.?The mice were maintained at room temperature 72° ± 2 °F, humidity 50 ± 10% and a 14 h light /10 h dark cycle with the dark cycle starting at 18:00 h. Water was supplied ad libitum.?The mice were randomized into the treatment arms to achieve a normal weight distribution.?PZ-2891 was formulated in 30% Captisol, and was administered by oral gavage at 12 h intervals for 5 doses.?The mice were euthanized and tissues harvested 4 h after the last dose.?The tissue samples were used for total CoA, pantothenate and pantazine determinations.?Blood was collected from euthanized animals, plasma or serum was prepared and stored frozen until analysis.?Organs, including liver, forebrain, and hindbrain were quickly excised from euthanized animals and immediately flash frozen in liquid N2 or immersed in RNAlater overnight prior to freezing.?Forebrain and hindbrain regions were identified.?Total CoA was determined using 20–50 mg of tissue (liver, forebrain or hindbrain) homogenized in 2 ml of 1 mM KOH.?The pH was adjusted to 12.0 with 0.25 M KOH, and incubated at 55 °C for 2 h.?The pH of the sample was adjusted to 8.0, and the samples were derivatized with monobromobimane (mBBr) and analyzed by HPLC equipped with a fluorescence detector