Pharmacokinetics, distribution, metabolism, excretion and safety characterization of ZJCK-6-72: novel DYRK1A inhibitor with optimized brain exposure for Alzheimer’s disease therapy

Developing effective drugs for Alzheimer’s Disease (AD) is critically limited by insufficient brain exposure. To address this, structural optimization was employed to balance physicochemical properties and enhance blood-brain barrier (BBB) permeability, resulting in the development of ZJCK-6-72, a novel DYRK1A inhibitor. This study aims to comprehensively evaluate the drug-like properties and safety profile of ZJCK-6-72.MethodsA comprehensive in vitro and in vivo ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling of ZJCK-6-72 was conducted. Key assessments included pharmacokinetics, tissue distribution studies in rats, plasma protein binding assays, and metabolic stability testing. Additionally, acute toxicity was evaluated to determine the safety margin, and enzyme inhibition assays were performed to assess potential drug-drug interactions.ResultsZJCK-6-72 exhibited excellent oral bioavailability (78.03%) and extensive tissue distribution in rats. Notably, the compound demonstrated substantially enhanced brain penetration, with a brain-to-plasma ratio ranging from 1.92 to 4.63. The unbound brain-to-plasma partition coefficient (Kp, uu) was determined to be 3.50, significantly exceeding unity. Metabolic studies indicated a shift towards CYP1A2 and CYP2C19 mediated pathways, with concentration-dependent inhibition observed (IC50 ≈ 1.8 μM). The acute toxicity assessment revealed an LD50 of 233.9 mg/kg bodyweight.DiscussionThe high Kp, uu value indicates that the efficient brain entry of ZJCK-6-72 is likely driven by active uptake mechanisms rather than simple passive diffusion, confirming its ability to effectively evade efflux transporters. Although the inhibition of CYP1A2 and CYP2C19 suggests a potential for mechanism-based auto-inhibition, the acute toxicity profile demonstrates an acceptable safety margin for therapeutic development.ConclusionZJCK-6-72 displays an optimized pharmacokinetics profile characterized by superior unbound brain exposure. These findings support the potential of ZJCK-6-72 as a promising lead candidate for CNS-targeted AD therapy.