Aqueous solubility of compound

Aqueous solubility of compounds is a critical issue, since NMR screens must be run at relatively high compound concentrations, anywhere from millimolar for NOE, chemical shift perturbation or affinity NMR methods [3, 5, 103-108] to ca. 50 pM for saturation-... 

It has been shown above that basic molecular descriptors like size, H-bond acidity-basicity and polarisability-dipolarity can be used to describe various water-solvent partitions, biological partition processes, and can be used even for estimating the aqueous solubility of compounds. However, the measurement of these molecular descriptors is very time-consuming, and it is not easy to access existing data. Promising results revealed that the fast reversed-phase chromatographic retention data (CHI) could be correlated with such descriptors with a good overall statistical fit (low standard error. 

This equation has been mainly used in correlations of aqueous solubility of compounds, octanol/water partition coefficients and some other partition parameters together with some biological properties [Kamlet et al., 1984 Kamlet et al., 1986a Kam-let et al, 1987a Kamlet et al, 1987c Kamlet et al, 1988c]. 

An interesting further development of regression trees is the software CUBIST [239], which combines recursive partitioning with linear regression. The predicting functions are RT with LM at terminal nodes. In [40] the aqueous solubility of compounds is modeled using this method. 

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. ... 

Catana, C., Gao, H., Orrenius, C., Stouten, P. F. Linear and nonlinear methods in modeling the aqueous solubility of organic compounds. 

True zwitterionic compounds are rare among drugs. The oral absorption of truly zwitterionic compounds is poor unless the compound is a substrate for an absorptive biological transporter as in an a-amino acid which is a substrate for the PepTl nutrient transporter. The aqueous solubility of a true zwitterionic compound will be at a minimum at the isoelectric point which unfortunately for many compounds happens close to the neutral pH at which oral absorphon occurs. Species extrapolation predicting oral absorphon and pk/pD from preclinical animal tests to man are difficult for zwitterions. 

McElroy, N. R., Jurs, P. C. Prediction of aqueous solubility of heteroatom-containing organic compounds from molecular structure. J. Chem. Inf. Comput. Sd. 2001, 41,1237-1247. 

S. Prediction of aqueous solubility of organic compounds using a quantitative structure-property relationship. J. Pharm. Sd. 2002, 91,1838-1852. 

Wakita, K., Yoshimota, M., Miyamoto, S., Watanabe, H. A method for calculation of the aqueous solubility of organic compounds by using new fragment solubility constants. Chem. Pharm. Bull. 1986, 34, 4663 681. 

In general the rate of false negatives are by definition difficult to ascertain. There are two general approaches to get a handle on false negatives. The first approach is based on what is known about the aqueous solubility of screening compounds since truly active compounds out of solution are the most common cause of false negatives. One can infer that perhaps 15% of true positives will be missed in an HTS. This inference comes from an analysis of the concordance or lack of concordance between nominal concentrations in DMSO stocks and nominal... 

IkB kinase-p is a key regulatory enzyme in the NF-kB pathway, and inhibition of this enzyme has the potential for yielding treatments for inflammatory and autoimmune diseases. Morwick et al. [53] report on the optimization of a pM IKKp inhibitor with low aqueous solubility, moderate human liver microsome stability, and inhibition of several CYPs (3A4, 2C9, 1A2) with pM potencies. Modulation of the thiophene core (other thiophene isomer, pyrimidine and oxazole) produces compounds of similar potency to the hit. Fusing the 5-phenyl moiety to the thiophene to form a thieno[2,3-b]pyridine core increases aqueous solubility of the series as well as reduces the CYP liability. While the optimized compound still shows pM IKK(S potency, the aqueous solubility, HLM stability and CYP profiles are much improved. A pharmacophore model was generated that enabled scaffold hopping to yield this new chemotype (Scheme 7). 

Chlorogenic acid forms a 1 1 complex with caffeine, which can be crystallized from aqueous alcohol and yields very little free caffeine on extraction with chloroform. Other compounds with which caffeine will complex in this way include isoeugenol, coumarin, indole-acetic acid, and anthocyanidin. The basis for this selection was the requirement for a substituted aromatic ring and a conjugated double bond in forming such a complex. This kind of complex does modify the physiological effects of caffeine.14 Complex formation will also increase the apparent aqueous solubility of caffeine in the presence of alkali benzoates, cinnamates, citrates, and salicylates.9... 

Two sensibly priced commercial databases for solubility exist [366,507], An article in the journal Analytical Profiles of Drug Substances carries solubility data [496]. Abraham and Le [508] published a list of intrinsic aqueous solubilities of 665 compounds, with many ionizable molecules. It is difficult to tell from published lists what the quality of the data for ionizable molecules is. Sometimes, it is not clear what the listed number stands for. For example, Sw, water solubility, can mean several different things either intrinsic value, or value determined at a particular pH (using buffers), or value measured by saturating distilled water with excess compound. In the most critical applications using ionizable molecules, it may be necessary to scour the original publications in order to be confident of the quality of reported values. 

Substrate can be added to the cultures as a solid, a suspension, or a solution in DMSO, methanol, ethanol, acetonitrile or water. As the microbial culture generally has high tolerance toward organic solvents, there is less restriction on the choice and amount of solvent to be used for dispensing the substrate. Aqueous solubility of substrates normally will not affect compound loading, as a compound with poor aqueous solubility will likely be absorbed by the cells and still be subjected to biotransformation. 

Changes in the method of compound distribution for biological assays and therefore changes in apparent aqueous solubility and compound concentration. 

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],... 

At least two correlation studies on the aqueous solubilities of liquid organic compounds have been published [18, 19], and in each case an excellent correlation (r > 0.9) was obtained. For both liquid and solid compounds, log P or CLOGP accounts for a major portion of variance in water solubility [3, 4, 20]. However, the... 

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