Permeability and aqueous solubility

Most drugs are ionized in aqueous solution (Table 2.1), and can therefore exist in a neutral or a charged state, depending on the pH of the local environment. Molecules are more lipophilic when neutral than when charged. Ionization is expressed by the aqueous ionization constant, pKa. As pointed out below, log D is a p Independent term for ionizable drugs. Permeability and aqueous solubility are also pKa-dependent. Lipophilicity, pKa, permeability through artificial membranes and... 

It must be noted that permeability and aqueous solubility are also pKa dependent. Thus in the last twenty years, the need for accurate and precise pKa values in the drug discovery process has fueled the development of methods to measure pKa values and to predict them from structure. Measurements of log D and pKa have been well addressed by Corner. For further detailed discussion of pKa values and their prediction methodologies, readers are referred to an important publication of Fraczkiewicz. A few common methods for the pKa values prediction are summarized in Table 7.1. The most commonly used programs for the pKa calculation are listed in Table 7.2. 

Based on their low permeability and low solubility characteristics, it might be expected that dass 4 compounds would hardly be effective drugs. However, a considerable number of class 4 compounds may be misclassified in terms of in vivo characteristics, as solubility in aqueous solutions may not reflect solubility in gut content. For example, the FDA publication [72] and others have suggested that solubility measurements in surfactant-containing solution may be a more appropriate basis for the solubility criteria. Oral bioavailability for true class 4 compounds is already minimal so that any transporter effect could be relevant, as a small increase in bioavailability (e.g., from 2 to 4%) would make a significant difference [61]. 

Permeability-molecular surface area-in vitro-in silico model The permeability values obtained from the Caco-2 cell monolayers have been traditionally used to devise in silico models for the prediction of drug absorption. In this paper, the use of molecular surface areas as descriptors of permeability and solubility will be reviewed. Moreover, a virtual filter for the prediction of oral drug developability based on the successful combination of in vitro and in silico models of drug permeability and aqueous drug solubility will be discussed. 

Principal component analysis (PCA) is a mathematical method for dimensionality reduction that allows for multidimensional datasets to be visualized using two- or three-dimensional plots with minimal loss of information [1,2]. When applied in the context of diversity-oriented synthesis, PCA is primarily used to visualize similarities and differences within collections of compounds based on structural and physicochemical parameters, and can be leveraged in library design [3]. Molecular weight, stereocenters, rotatable bonds, hydrophobicity, and aqueous solubility are a few examples of parameters commonly included in such analyses. Herein, we selected 20 structural and physicochemical parameters for analysis based on previously identified correlations of these parameters with oral bioavailability, cell permeability, solubility, and binding selectivity, as well as their ability to distinguish synthetic drugs... 

Bergstrom, C. A. S. Computational models to predict aqueous drug solubility, permeability and intestinal absorption. Exp. Opin. Drug Metab. Toxicol. 2005, 1, 513-527. 

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

Drugs in Class II have low aqueous solubility (but high membrane permeability), and any factor affecting dissolution rate would be expected to have an impact on the absorption of such compounds. Factors that are noted in Fig. 11, such as fluid pH, volume and viscosity, and bile secretion (especially in response to fatty foods), might be expected to play a role in dissolution rate and thereby affect absorption. Compounds that fall into this class include carbamazepine, cyclosporin, digoxin, griseofulvin, and spironolactone. Food would be expected to exert a potentially significant affect on... 

Drugs in Class III have good aqueous solubility but poor membrane permeability (e.g., bidisomide, bispho-sphonates, captopril, and furosemide). Food and food components would only be expected to influence absorption of drugs in this class if they affected some aspect... 

Class IV drugs have low aqueous solubility and poor membrane permeability and as such are often considered as poor drug candidates for oral administration. Other routes of administration may need to be considered. For example, neomycin falls into this category, and its oral use is to achieve sterilization of the gut. There is too little information about these compounds and the effect of food to offer general observations. 

Aqueous solubility, potency and permeability are three factors under medicinal chemistry control that must be optimized to achieve a compound with acceptable oral absorption. Typically, a lead (chemistry starting point) is deficient in all three parameters. The inter-relationships of these three parameters has been described in a series of publications from Pfizer researchers [7, 8]. Figure 9.1 depicts graphically the minimum acceptable solubility as a function of projected clinical potency and intestinal permeability. A minimum thermodynamic aqueous solubility of 52... 

In the current era with widespread problems of poor solubility [4] a compound (drug) with average permeability and a projected clinical potency of 1 mg kg-1 needs a minimum aqueous solubility of 50-100 jug mL-1 to avoid the use of nonstandard solubility fixing formulation technology. The guidelines published by Pfizer s Curatolo on maximum absorbable dose are an excellent guide for the combination of permeability, solubility and potency required in an orally active drug [8],... 

QMPRPlus was used to generate in silico estimates of log P, aqueous solubility, and human jejunal permeability from 3D molecular structures. The predictive... 

A series of non-ATP competitive, PH-domain-dependent allosteric inhibitors selective for AKT-1 and AKT-2 have previously been described [34]. Recently, new analogs, such as 22 and 23, were reported as potent and selective AKT-1 and AKT-2 inhibitors with improved aqueous solubility and cell permeability [35]. 

Lead optimization of new chemical entities (NCEs) based on pharmacokinetic behavior plays a major role in modern drug discovery. Despite advancement of drug delivery methods, the oral route remains the most frequent route of administration for approved new drugs. Therefore, during lead optimization it is essential to identify NCEs with sufficient oral absorption predicted using a variety of in vitro and in vivo assays. It is well recognized that in order for a NCE to achieve reasonable oral absorption, it will need to have adequate aqueous solubility, as well as intestinal permeability [1], Recent advancements in chemistry, such as parallel and combinatorial synthesis, have resulted in a multifold increase in the number of compounds that are available for evaluation in new drug discovery. Furthermore, a variety of improved structural chemistry... 

Compounds with acceptable pharmaceutical properties, in addition to acceptable biological activity and safety profile, are considered "drug-like" or developable. Typical acceptable pharmaceutical properties for oral delivery of a drug-like molecule include sufficient aqueous solubility, permeability across biological membranes, satisfactory stability to... 

Low or poor aqueous solubility is a relative term. Therefore, the solubility of a compound must be considered together with its dose and permeability. A simple approach to assess oral absorption with a drug substance could be the calculation of its maximum absorbable dose (MAD) 69... 

Bioavailability can be assessed early in the discovery process by combining data from a number of independent in vitro assays run as part of a pharmaceutical properties profile. These assays generally include some measurement of aqueous solubility, lipophilicity, cell or membrane permeability, and metabolic stability. In most cases, proper interpretation of... 

Approximately 300 drugs were tested in aqueous solubility, log D, and apparent permeability assays. Compounds having low values for solubility, or apparent permeability, or extreme log D values were flagged. The frequency of compounds with flags in each human absorption (%) bin is shown. 

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