Towards the rational design of novel drugs based on solubility, partitioning/distribution, biomimetic permeability and biological activity exemplified by 1,2,4-thiadiazole derivatives.

Novel 1,2,4-thiadiazole derivatives as potent neuroprotectors were synthesized and identified. Their ability to inhibit the glutamate stimulated Ca2+ uptake was investigated. The solubility of thiadiazoles was measured in a buffer solution (pH 7.4) at 298 K. The distribution coefficients in 1-octanol/buffer (pH 7.4) and 1-hexane/buffer (pH 7.4) immiscible phases as model systems imitating the gastrointestinal tract epithelium and the blood-brain barrier were determined. Permeation experiments the new Permeapad™ barrier using Franz diffusion cells were conducted and the apparent permeability coefficients were obtained. The influence of the compound structure on the physicochemical properties determining the bioavailability of drug-like substances was revealed. Solubility-permeability interplay has been assessed to evaluate potential bioavailability of the compounds studied.

Adamantane derivatives of sulfonamides: sublimation, solubility, solvation and transfer processes in biologically relevant solvents.

Eight adamantane derivatives of sulfonamides were synthesized and characterized. Temperature dependencies of saturation vapor pressure were obtained using the transpiration method and thermodynamic functions of the sublimation processes were calculated. Solubility values of the selected compounds in buffer (pH 7.4), 1-octanol and 1-hexane were determined at different temperatures using the isothermal saturation method. Thermophysical characteristics of fusion processes (melting points and fusion enthalpies) of the substances were studied using the DSC method. Transfer processes from buffer to 1-octanol, from buffer to 1-hexane and 1-hexane to 1-octanol were analyzed. The impact of the molecules' structural modification on sublimation, solubility and solvation/hydration processes in the solvents was studied. Correlation equations connecting the thermodynamic functions with physicochemical descriptors were obtained.

The impact of structural modification of 1,2,4-thiadiazole derivatives on thermodynamics of solubility and hydration processes.

The influence of a structural modification on thermodynamic aspects of solubility and hydration processes of 1,2,4-thiadiazole drug-like compounds was investigated. A substitution in the phenyl ring of the 1,2,4-thiadiazole molecule leads to a significant decrease of the solubility of these compounds. In order to rationalize the relationship between the structures of 1,2,4-thiadiazoles and their solubility, the latter was considered in terms of two fundamental processes: sublimation and hydration. It was found that for most of the compounds solubility decline is a result of a differently directed action of the sublimation and hydration contributions, i.e., the introduction of substituents leads to the simultaneous growth of the sublimation Gibbs energy and decrease in the hydration Gibbs energy.

[Method for determining kallikrein of tissue origin in blood plasma and its clinical significance]. / Metod opredeleniia kallikreina tkanevogo proiskhozhdeniia v plazme krovi i ego znachenie dlia kliniki.

Based on a study of the kininogenase activity of the total plasma kallikrein in the presence of 3 concentrations of the soybean inhibitor trypsin (0.5, 1.0, 10.0 micrograms/ml) one can measure at a time the activity of tissue kallikrein (without specifying the source) and the activity of 3 forms of plasma kallikrein, including its adsorption on kaolin that characterizes the conformational structure of the enzyme. Examination of 10 healthy subjects and 136 patients revealed a 10 to 20-fold increase in the content of tissue kallikrein in plasma of 70% of diabetes mellitus patients and a 2.5 to 3-fold elevation in 50% of patients with chronic occupational bronchitis, and in 30% of patients suffering from chronic hepatitis. The method suggested makes it possible to have a better insight into the physiological and pathogenetic role of the kinin system and may be used for laboratory control over the treatment efficacy.