RESUMEN
Penetration through the blood-brain barrier (BBB) is desirable in the case of potential pharmaceuticals acting on the central nervous system (CNS), but is undesirable in the case of drug candidates acting on the peripheral nervous system because it may cause CNS side effects. Therefore, modeling of the permeability across the blood-brain barrier (i.e., the logarithm of the brain to blood concentration ratio, log BB) of potential pharmaceuticals should be performed as early as possible in the preclinical phase of drug development. Biomimetic chromatography with immobilized artificial membrane (IAM) and the quantitative structure-activity relationship (QSAR) methodology were successful in modeling the blood-brain barrier permeability of 126 drug candidates, whose experimentally-derived lipophilicity indices and computationally-derived molecular descriptors (such as molecular weight (MW), number of rotatable bonds (NRB), number of hydrogen bond donors (HBD), number of hydrogen bond acceptors (HBA), topological polar surface area (TPSA), and polarizability (α)) varied by class. The QSARs model established by multiple linear regression showed a positive effect of the lipophilicity (log kw, IAM) and molecular weight of the compound, and a negative effect of the number of hydrogen bond donors and acceptors, on the log BB values. The model has been cross-validated, and all statistics indicate that it is very good and has high predictive ability. The simplicity of the developed model, and its usefulness in screening studies of novel drug candidates that are able to cross the BBB by passive diffusion, are emphasized.
Asunto(s)
Barrera Hematoencefálica , Relación Estructura-Actividad Cuantitativa , Biomimética , Cromatografía , Membranas Artificiales , Permeabilidad , Preparaciones FarmacéuticasRESUMEN
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.
Asunto(s)
Antineoplásicos/química , Barrera Hematoencefálica/metabolismo , Cromatografía Líquida de Alta Presión/métodos , Cromatografía de Fase Inversa/métodos , Analgésicos/química , Analgésicos/farmacología , Antineoplásicos/farmacología , Antivirales/química , Antivirales/farmacología , Azoles/química , Transporte Biológico , Barrera Hematoencefálica/química , Modelos Lineales , Modelos Moleculares , Permeabilidad , Relación Estructura-Actividad Cuantitativa , Reproducibilidad de los ResultadosRESUMEN
A stopped-flow HPLC method was developed to evaluate configurational and chemical stability of pharmaceutical compounds employing immobilized artificial membranes (IAM) column to simulate conditions that pharmaceutical compounds will meet in vivo. The method was applied to recent developed chiral 5-arylbenzothiadiazine derivatives possessing high positive allosteric modulatory (PAM) activity on AMPA receptor. In particular the stopped-flow HPLC method developed used a chiral column to separate single enantiomer of the compounds that are forced into an IAM column where configurational and chemical stability was evaluated in simulated gastrointestinal fluids (pH 1.2 and 6.8 at 37.5 °C) to simulate in vivo conditions. The results were compared to those obtained by dynamic and off-column methods to evaluate the effects of stationary phases on kinetic constant of enantiomerization and hydrolysis. The results suggested that the phospholipids environment of IAM stationary phases, which mimes biological membrane, greatly influence the hydrolysis process increasing the chemical stability of tested compounds while no influence on enantiomerization kinetic was observed. Therefore it is possible to suppose that 5-arylbenzothiadiazine derivatives should not hydrolysed in vivo while they should rapidly racemized in aqueous solvents. The method could represents a rapid and value tool to predict chemical and configurational stability of new chemical entities to decrease the number of animal studies.