Presentation on theme: "Surface activity profiling: a novel physicochemical tool for the prediction of blood-brain-barrier permeation Paavo K.J. Kinnunen Helsinki Biophysics &"— Presentation transcript:
Surface activity profiling: a novel physicochemical tool for the prediction of blood-brain-barrier permeation Paavo K.J. Kinnunen Helsinki Biophysics & Biomembrane Group Institute of Biomedicine University of Helsinki Finland
Pharmocokinetics Challenge: Design good physicochemistry into the molecules as early as possible. What we know: Physicochemistry correlates with ADME/tox.
Outline 1.Existing assays logP, TPSA, CACO2, PAMPA,... 2.Amphiphilicity through surface activity Model justification Physicochemical parameters obtained 3. Overview on Delta-8 technology Features and specifications
Lipid bilayers: barrier for the entry of drugs into cells by passive diffusion
Ambiguous amphiphiles In order to be useful as a drug a compound has to dissolve in water hydrophilicity required has to permeate lipid bilayers lipophilicity required Hydrophilic part e.g. carboxylic acid derivatives Lipophilic part e.g. hydrocarbon chain
Air-water interface – a good model for lipid membranes Amphiphiles are strongly oriented in lipid membranes and in the air-water interface. Partitioning into both interfaces is mainly driven by the hydrophobic effect Air/water interface:Phospholipid bilayer:
Air-water interface: presence of multiple equilibria Partitioning Micellization Air Aqueous phase
Amphiphilicity is monitored through surface tension Maximum pull technique:
Looking at the hydrophobic effect in action... ~1/K aw CMC Slope= 1/A s =d /RTdlnc
Compound structure must be optimized for optimum performance. Can surface activity profiling help?
Importance of the interfacial area ”common” phys-chem 100010000K aw >0.010.004CMC 14678AsAs Amphiphilicity profiling 4136TPSA 3.23.3LogP 308.4447.8MW -+CNS Phenyl butazone Hydroxyzine
Prerequisites for passive permeation... NalbuphineDisopyramide CNS+- common physchem MW357340 LogP1.612.96 TPSA73.259.2 surface activity profiling K AW 461195 A S (Å 2 )65129
Spatial arrangement does matter PropranololMetoprolol CNS+CNS-
Literature for BBB-permeability P. Suomalainen et al., Surface Activity Profiling of Drugs Applied to the Prediction of Blood-Brain Barrier Permeability. J. Med.Chem., 47:1738-1788,2004. H. Fischer et al., Blood-Brain Barrier Permeation; Molecular Parameters Governing Passive Diffusion. J.Membr.Biol., 165:201-211, 1998 A.Seelig et al. A Method to Determine the Ability of Drugs to Diffuse Through the Blood-Brain Barrier. Proc. Natl.Acad.Sci., 91:68-72, 1994