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

Background/Objectives: Alzheimer's disease (AD) is a neurodegenerative disorder with a high incidence but limited agents. Herein, PZ-2891 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. Methods: 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 PZ-2891. 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 PZ-2891's PK properties in SD rats through a triple quadrupole liquid chromatography-mass spectrometry (LC-MS/MS) instrument. Results: PZ-2891 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 PZ-2891 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%. Conclusions: These findings suggest that PZ-2891, an agonist of PANK2, is a novel and potential candidate agent for AD with excellent efficacy and PK properties.