Predicting the Blood-Brain Barrier Permeability of New Drug-Like Compounds via HPLC with Various Stationary Phases.

Małgorzata Janicka,Małgorzata Sztanke,Krzysztof Sztanke

doi:10.3390/molecules25030487

Małgorzata Janicka, Małgorzata Sztanke + Show 1 more

Open Access

https://doi.org/10.3390/molecules25030487

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Abstract

The permeation of the blood-brain barrier is a very important consideration for new drug candidate molecules. In this research, the reversed-phase liquid chromatography with different columns (Purosphere RP-18e, IAM.PC.DD2 and Cosmosil Cholester) was used to predict the penetration of the blood-brain barrier by 65 newly-synthesized drug-like compounds. The linear free energy relationships (LFERs) model (log BB = c + eE + sS + aA + bB + vV) was established for a training set of 23 congeneric biologically active azole compounds with known experimental log BB (BB = Cblood/Cbrain) values (R2 = 0.9039). The reliability and predictive potency of the model were confirmed by leave-one-out cross validation as well as leave-50%-out cross validation. Multiple linear regression (MLR) was used to develop the quantitative structure-activity relationships (QSARs) to predict the log BB values of compounds that were tested, taking into account the chromatographic lipophilicity (log kw), polarizability and topological polar surface area. The excellent statistics of the developed MLR equations (R2 > 0.8 for all columns) showed that it is possible to use the HPLC technique and retention data to produce reliable blood-brain barrier permeability models and to predict the log BB values of our pharmaceutically important molecules.

Highlights

The biological activity of drugs depends primarily on their pharmacokinetics
In our investigations in which we modelled the blood-brain permeation of 65 biologically active molecules, the chromatographic lipophilicity (Table 2), polarizability (α) and topological polar surface area (TPSA) (Table 5) were considered
The standardized coefficients obtained for particular descriptors confirmed that the compound polarity, i.e., dipolarity/polarizability (S), hydrogen bond acidity (A) and hydrogen bond basicity (B) decreases the blood-brain barrier (BBB)

Summary

Introduction

The biological activity of drugs depends primarily on their pharmacokinetics. The expected pharmacological effect of a given drug can be observed if the pharmacokinetic processes provide its high concentration within the range of the receptor. The amount of drug in tissue and the time that remains an effective concentration depend on the fundamental processes that make up the pharmacokinetic phase of the drug’s action, i.e., liberation (L), absorption (A), distribution (D), metabolism (M) and excretion (E). Since most drugs must pass through at least one cell membrane to provide the desired effect, for the rational design of drugs, it is vitally important to understand and to be able to predict the solute partitioning in the biomembranes. Drugs can cross membranes by passive or active transport [1,2,3]. While active transport is determined by compounds’ affinities for specific transporters and it uses energy, the most

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Discussion

Conclusion