Biomimetic ADME Profiling of Multifunctional Biphenylalkoxyamine-Related Histamine H3 Receptor Ligands with Anti-Alzheimer Potential

Multifunctional histamine H3 receptor (H3R) ligands with cholinesterase inhibitory activity are being explored as potential Alzheimer’s disease therapeutics, but their interactions with biological membranes and associated ADME properties require parallel evaluation. Here, six structurally related alkoxyamine H3R ligands were characterized using an HPLC-based biomimetic workflow centered on immobilized artificial membrane (IAM) chromatography to assess phospholipid affinity, estimate passive blood–brain barrier permeability and human intestinal absorption. IAM measurements were complemented by HSA/AGP plasma protein binding, biomimetic distribution descriptors, plasma stability, chromatographic lipophilicity at pH 7.4 and solubility in JP1 (pH 1.2), JP2 (pH 6.8), and phosphate buffer (pH 7.4). The IAM models classified all six ligands as CNS-positive and predicted high intestinal absorption, while CHIIAM values indicated strong membrane affinity. After 24 h, 77.5–89.5% and 62.2–80.5% parent compound remained in human and rat plasma, respectively. Solubility remained measurable across all three media. Integrated consideration of membrane-related ADME properties and previously reported pharmacology prioritized compounds (6), (5) and (2). Compound (6) showed the strongest overall potency–developability balance, although the biomimetic membrane predictions require confirmation in direct permeability, transporter, and in vivo pharmacokinetic studies.