Pharmacokinetic and Pharmacodynamic Evaluation of PZ-2891, an Anti-Alzheimer’s Disease Agonist of PANK2

<b>Background/Objectives:</b> Alzheimer's disease (AD) is a neurodegenerative disorder with a high incidence but limited agents. Herein, <b>PZ-2891</b> was discovered as a novel anti-AD candidate. Both in vivo and in vitro pharmacodynamic (PD) studies and pharmacokinetic (PK) properties were investigated and illustrated in this research. <b>Methods</b>: A computer-generated random number table was used to divide mice into various groups randomly. Injecting Aβ into the mice hippocampus to mimic AD-like pathologies, neurobehavioral tests, including the Morris maze, Y maze, open field test (OFT) and novel object recognition (NOR), were operated to evaluate the cognitive improvement in <b>PZ-2891</b>. D-galactose (D-gal), okadaic acid (OA) and lipopolysaccharide (LPS) were employed to trigger neural injuries in vitro. A reliable analytic method was developed to profile <b>PZ-2891</b>'s PK properties in SD rats through a triple quadrupole liquid chromatography-mass spectrometry (LC-MS/MS) instrument. <b>Results: PZ-2891</b> markedly alleviated cognitive impairment in the Aβ-induced model mice. It also protected nerve cells from oxidative stress and inflammatory injuries and significantly reduced AD-typical pathological biomarkers. The PK results showed that <b>PZ-2891</b> was exposed rapidly in both plasma and brain, with a brain-to-blood ratio of around 0.59, C_max of around 454.50 ± 151.35 ng/mL, T_max of around 0.49 ± 0.15 h and oral bioavailability of around 19.74 ± 6.78%. <b>Conclusions:</b> These findings suggest that <b>PZ-2891</b>, an agonist of PANK2, is a novel and potential candidate agent for AD with excellent efficacy and PK properties.