Biomimetic ADME Profiling of Multifunctional Biphenylalkoxyamine-Related Histamine H₃ Receptor Ligands with Anti-Alzheimer Potential.
4 affiliations
- 1Department of Pharmaceutical Sciences, University of Vienna, Josef-Holaubek-Platz 2, 1090 Vienna, Austria.
- 2Vienna Doctoral School of Pharmaceutical, Nutritional and Sport Sciences, University of Vienna, Josef-Holaubek-Platz 2, 1090 Vienna, Austria.
- 3Chair of Chemical Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna Str. 9, 30-688 Kraków, Poland.
- 4The Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC 3052, Australia.
Abstract
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.
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BibTeX
@article{simic2026biomimetic,
title = {{Biomimetic ADME Profiling of Multifunctional Biphenylalkoxyamine-Related Histamine H₃ Receptor Ligands with Anti-Alzheimer Potential.}},
author = {Stefan Simić and Dorota Łażewska and Predrag Kalaba and Judith Wackerlig-Damle and Thierry Langer},
journal = {Membranes},
year = {2026},
month = sep,
doi = {10.3390/membranes16100315},
url = {https://europepmc.org/article/MED/42930993},
note = {CC BY},
}
RIS
TY - JOUR
TI - Biomimetic ADME Profiling of Multifunctional Biphenylalkoxyamine-Related Histamine H₃ Receptor Ligands with Anti-Alzheimer Potential.
AU - Stefan Simić
AU - Dorota Łażewska
AU - Predrag Kalaba
AU - Judith Wackerlig-Damle
AU - Thierry Langer
PY - 2026
DA - 2026/09/25
JO - Membranes
DO - 10.3390/membranes16100315
UR - https://europepmc.org/article/MED/42930993
AB - 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.
SN - 2077-0375
ER -