Lead compounds intestinal permeability

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... 

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... 

However, several problems limit the use of these valuable compounds. The problem of lack of stability should first be resolved before using natural polyphenols in pharmaceutics or cosmetics. These compounds oxidize very quickly, leading to the appearance of unwanted colors and to a decrease in activity. Furthermore, many natural polyphenolic compounds present limited water solubility. This low solubility, often associated with low intestinal permeability and instability in the gastrointestinal tract (pH, enzymes, and other nutrients), results in insufficient oral bioavailability. Finally, the astringent and bitter taste of many polyphenolics should be masked before use in food or for oral pharmaceutical forms. 

A special case in dissolution-limited bioavailability occurs when the assumption of sink condition in vivo fails that is, the drug concentration in the intestine is dose to the saturation solubility. Class IV compounds, according to BCS, are most prone to this situation due to the combination of low solubility and low permeability, although the same could also happen for class II compounds, depending primarily on the ratio between dose and solubility. Non-sink conditions in vivo lead to less than proportional increases of bioavailability for increased doses. This is illustrated in Fig. 21.8, where the fraction of drug absorbed has been simulated by use of an compartmental absorption and intestinal transit model [35] for different doses and for different permeabilities of a low-solubility, aprotic compound. 

Despite the availability of other cell lines, Caco-2 cells remain the most widely used intestinal cell culture model at present. This model has provided valuable information necessary for lead optimization in the drug discovery process. However, it is important to understand that compounds with high permeability in this model are typically well absorbed, whereas compounds with low solubility and low permeability in this model may not necessarily be poorly absorbed in vivo. Although this type of positive selection limits the usefulness in providing a structure-permeability relationship, the Caco-2 model has the most effect in drug discovery when the screen is implemented early and in conjunction with other types of in vitro and in vivo permeability/absorption screens. 

In this project, compound A from a potential lead series was a neutral compound of MW 314 with low aqueous solubility (Systemic clearance, volume and AUC following a 0.5mg/kg intravenous dose to rats were well predicted (within twofold) from scaled microsomal clearance and in silica prediction of pKa, logP and unbound fraction in plasma. Figure 10.3a shows the predicted oral profile compared to the observed data from two rats dosed orally at 2mg/kg. The additional inputs for the oral prediction were the Caco-2 permeability and measured human fed-state simulated intestinal fluid (FeSSIF, 92(tg/mL). The oral pharmacokinetic parameters Tmax. Cmax. AUC and bioavailability were well predicted. Simulation of higher doses of compound A predicted absorption-limited... 

P = effective permeability, r = intestinal radius, and = residence time in the small intestine [2]. The critical assumptions in this relationship are (1) that the drug is in solution and hence available for transport across the intestinal membrane and (2) the drug is chemically stable in the gastrointestinal tract and not a substrate for proteolytic or metabolic enzymes in the intestinal lumen or gut mucosa. These are highly simplifying assumptions. The inappropriate use of Eq. (2) to calculate absorption for compounds that are limited by solubility, instability, or metabolism can lead to seriously erroneous and misleading conclusions. 

Permeability will restrict the absorption if the permeability coefficient through the enterocytes is low, leading to only a fraction of the compound in solution that has been transported over the epithelium during the transit time in the small intestine. Both solubility and permeability are dependent on the physicochemical properties of the molecule, unfortunately in an opposed manner (Fig. 16-3). For instance, lipophilicity, which is the major driving force for permeability, is one of the most restricting properties for aqueous solubility. 

Inhibition of protein phosphatases by OA class compounds leads to a rapid increase of phospho-rylated proteins in cells. This effect seems to be responsible for the diarrhea and the degenerative changes in absorptive epithelimn of small intestine induced by these toxins. In fact, the increased level of phosphorylated cytoskeletal proteins modifies the junctional elements between the intestinal epithelial cells controlling the permeability to solutes, which, in turn, results in passive loss of fluids. For more details about the diarrheic mechanism, see the in vitro activities section. 

With increasing importance being attached to the early detection of compounds likely to be problematic from an absorption, distribution, metabolism, and excretion (ADME) viewpoint, " at RPR we sought to apply computational measures for the prediction of intestinal absorption—a key requirement for an orally bioavailable compound—during the design of lead optimization libraries. To this end, we implemented the popular rule-of-5 criteria described by Lipinski et al. compound is deemed to fail the rule-of-5 check (and thereby to be possibly deficient from an oral absorption/permeability aspect) if it possesses two or more of the following features ... 

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