Lead compounds aqueous solubility

Combinatorial chemistry and parallel synthesis are now the dominant methods of compound synthesis at the lead discovery stage [2]. The method of chemistry synthesis is important because it dictates compound physical form and therefore compound aqueous solubility. As the volume of chemistry synthetic output increases due to combinatorial chemistry and parallel synthesis, there is an increasing probability that resultant chemistry physical form will be amorphous or a neat material of indeterminate solid appearance. There are two major styles of combinatorial chemistry - solid-phase and solution-phase synthesis. There is some uncertainty as to the true relative contribution of each method to chemistry output in the pharmaceutical/biotechnology industry. Published reviews of combinatorial library synthesis suggest that solid-phase synthesis is currently the dominant style contributing to about 80% of combinatorial libraries [3]. In solid-phase synthesis the mode of synthesis dictates that relatively small quantitities of compounds are made. 

The best-known carboxylate of lead(II) is lead(II) acetate, (CH3COO)2Pb. 3H2O (sugar of lead), made by dissolving lead(II) oxide in acetic acid. The salt is very soluble in water (1 g dissolves in about 1 -6 ml of cold water or 0-5 ml of boiling water). Solutions are only partly ionizedio , which accounts for the strong solvent effect of acetates upon lead compounds. (Aqueous solutions of lead(II) acetate freely dissolve lead(II) oxide.)... 

Another example that focuses on the use of DSE analysis is to model chemical properties such as predicting the aqueous solubility of compounds." Aqueous solubility provides an example of a physicochemical property that can be addressed at the level of structurally derived chemical descriptors. Because the aqueous solubility of many compounds is known, an accurate and sufficiently large dataset can be accumulated for constructing and evaluating predictive models. In addition, problems surrounding solubility remain a significant issue for lead identification and optimization in pharmaceutical research. ... 

Lead chromates are prepared by precipitation techniques from soluble salts ia aqueous media. The raw material Hst iacludes a number of different lead compounds, eg, Htharge, lead nitrate, basic lead acetate, basic lead carbonate, as well as acids, alkahes, sodium bichromate, and sodium chromate. The typical reaction can be represented by the foUowiag equation ... 

Many other metal thiosulfates, eg, magnesium thiosulfate [10124-53-5] and its hexahydrate [13446-30-5] have been prepared on a laboratory scale, but with the exception of the calcium, barium [35112-53-9] and lead compounds, these are of Httle commercial or technical interest. Although thaHous [13453-46-8] silver, lead, and barium thiosulfates are only slightly soluble, other metal thiosulfates are usually soluble in water. The lead and silver salts are anhydrous the others usually form more than one hydrate. Aqueous solutions are stable at low temperatures and in the absence of air. The chemical properties are those of thiosulfates and the respective cation. 

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... 

When a NAPL reaches the subsurface, it may by subject to mechanical forces that lead to the formation of a mixed NAPL-water micro-/nanoemulsion characterized by the presence of micro- and nanodroplets of organic compounds. These micro- and nanoemulsions are transparent or translucent systems, kinetically (nano-) or thermodynamically (micro-) stable, and display an apparent increase in aqueous solubility as compared to the intrinsic solubility of the NAPL itself (Tadros 2004). The very small droplet size (50-200 nm in the case of a nanoemulsion) causes a large reduction in the force of gravity, enabling the system to remain dispersed and... 

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... 

The octanol/water coefficient (log P) is the standard molecular descriptor used to provide the chemical property of the hydrophobicity of a molecule. Compounds with high partition coefficients usually have very low aqueous solubility. This will decrease the chance of attack by hydroxyl radicals and lead to a lower rate constant. Nevertheless, the linear relationships with log P do not reproduce similar trends of several chemical classes such as alkane and phenol. They could be either positive or negative linear relationships. Alkene (R2 < 0.67), benzene (R2 < 0.78), carboxylic acid (R2 < 0.74), and halide (R2 < 0.55) classes do not provide significant correlations. 

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