Solubility drug-likeness

In hit finding, a large number of compounds, the so-called library, is screened v. a target to identify components that bind. Libraries can meet different types of requirements, and efforts are made to optimize them with respect to diversity, solubility, drug-like character (see Table 1), and the synthetic accessibility of the compounds they contain. Substance libraries can contain small organic fragments, synthetic compounds of diverse chemical structures, or natural products. ... 

Venous drainage from the mouth is to the superior vena cava, which protects highly soluble drugs like nitroglycerin/rom rapid hepatic first-pass metabolism. If a tablet of nitroglycerin were swallowed, the accompanying hepatic metabolism would be sufficient to prevent the appearance of any active nitroglycerin in the systemic circulation. 

Many drug-like molecules have aromatic substituents and thus have limited aqueous solubility. A routine practice is to dissolve stock drugs in a solvent known to dissolve many types of molecular structures. One such solvent is... 

Lipinski, C. A. (2000). Drug-like properties and the causes of poor solubility and poor permeability. J. Pharmacol. Tox. Meth. 44 235-249. 

Lipinski CA. Drug-like properties and the causes of poor solubility and poor... 

Blocking the conversion to DA would appear stupid unless this could be restricted to the periphery. More dopa would then be preserved for entry into the brain, where it could be decarboxylated to DA as usual. Drugs like carbidopa and benserazide do precisely that and are used successfully with levodopa. They are known as extracerebral dopa decarboxylase inhibitors (ExCDDIs). Carbidopa (a-methyldopa hydrazine) is structurally similar to dopa but its hydrazine group (NHNH2) reduces lipid solubility and CNS penetration (Fig. 15.4). 

Lipinski, C.A. (2000) Drug-like Properties of Poor Solubility and Poor Permeability. Journal of Pharmacological and Toxicological Methods, 44(1), 235-249. 

Interpretation of Measured Solubility of lonizable Drug-Like Compounds can be Difficult... 

This chapter considered ionizable drug-like molecules. Absorption properties that are influenced by the pKj were explored. The impact of the pKj-absorption relationship on key physicochemical profiling underlying absorption (solubihty, per-meabihty and ionization) was examined in detail and several simpUfying equations were discussed. The various diff relationships considered in the chapter are systematized in Table 3.2. Table 3.3 summarizes the apparent pfQ shift method for detecting aggregates in solubility profiles, when the apparent pff value derived from Henderson-Hasselbalch analysis of log S pH profile does not agree with the... 

Balakin, K., Savchuk, N., Tetko, I. In silica approaches to prediction of aqueous and DM SO solubility of drug-like compounds trends, problems and solutions. Curr. Med. Chem. 2006, 13, 223-241. 

Delaney [4,14] and Klamt [16] argued that for drug-like compound datasets only about 20% of the variance of log S arises from AG s. This is further confirmed by the study of Wassvik et al. [15] in which 77% of the variance is due to the solubility of the supercooled liquid. Hence, applying crude estimates by mean values or by QSAR approaches we can reasonably expect that the inaccuracies introduced in dmg solubility prediction by our theoretical ignorance of AG s is less than, or at least not much bigger than, the inaccuracies introduced by the estimates of the larger park i.e. the liquid solubility, and by the experimental difficulties in solubility measurement. 

The generic term of drug-likeness implies a number of other properties [24] such as aqueous solubility, metabolism, blood-brain barrier penetration and oral absorption which are covered by other chapters in this book. 

At the hit triage stage, it is most common to be able to characterize sets of compounds in a kinetic solubility assay. In the assessment and utilization of these data, the potential disconnects between kinetic and thermodynamic solubility must be considered. Low kinetic solubility for a series of compounds should lead a project team to be concerned about the behavior of compounds in biological assays and buffers, as well as the potential for optimizing drug-like properties in that series. Conversely, while high kinetic solubility is a desirable property, chemists should still remain cognizant of the need to assess thermodynamic solubility as compounds are further optimized. 

This book is written for the practicing pharmaceutical scientist involved in absorption-distribution-metabolism-excretion (ADME) measurements who needs to communicate with medicinal chemists persuasively, so that newly synthesized molecules will be more drug-like. ADME is all about a day in the life of a drug molecule (absorption, distribution, metabolism, and excretion). Specifically, this book attempts to describe the state of the art in measurement of ionization constants (p Ka), oil-water partition coefficients (log PI log D), solubility, and permeability (artificial phospholipid membrane barriers). Permeability is covered in considerable detail, based on a newly developed methodology known as parallel artificial membrane permeability assay (PAMPA). 

The value of Cs is the most critical parameter in determining the overall release rate from a given osmotic system. Indeed, its value will determine whether or not it is feasible to utilize an osmotic system to deliver a particular drug for a specified duration. The maximum release rate achievable is likely that seen with KC1. The relevant values for the parameters in Eq. (6) for OROS [10] are as follows A = 2.2 cm2, h = 0.025 cm, LpO = 2.8 X 10 6 cm2/(atm hr), Us = 245 atm, and Cs = 330 mg/mL. This translates to about 20 mg/hr or about 250 mg over a 24 hr period. This is for a highly water soluble drug with a high osmotic pressure differential. For drugs of moderate solubility—for example,... 

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