(Q) SAR study on the metabolic stability of steroidal androgens.

Metabolic stability is a key issue in the development of orally active androgens for Partial Androgen Deficiency in Aging Males (PADAM) and male contraception. Rates of metabolism in human hepatocyte suspensions provide useful information on the stability of compounds that undergo a first pass metabolism. We have derived a structure-pharmacokinetic relationship for a data set of 32 in-house steroidal androgens by means of the decision-trees technique. Volume, shape, number of rotatable bonds, and surface turned out to be the most important descriptors for classification. Only 2 of the 32 compounds were misclassified. The most stable compounds were classified in three leaf nodes on different branches of the tree, suggesting that higher metabolic stability can be achieved for the same substrate by different steric modifications. Further, it is generally assumed that the first step in cytochrome P450s oxidation reactions takes place by hydrogen abstraction to form a radical intermediate. An electronic model for hydrogen abstraction in steroidal androgens was, therefore, developed by means of ab initio calculations. Activation energies of steroid radical systems calculated as energy differences between the reactants equilibrium geometry energies and their corresponding transition states energies could be used to predict relative rates of metabolism to guide the design and redesign process of metabolically more stable steroidal androgens.

Application of (quantitative) structure-activity relationships to progestagens: from serendipity to structure-based design.

Progestagens are drugs, which are widely used in hormonal contraception and in hormone-replacement therapy. Since the natural hormone, progesterone, lacks oral activity, much effort has been devoted to finding analogues with improved oral activity and, preferably, higher potency and selectivity. A crystal structure of the hormone binding domain (HBD) region of the progesterone receptor (PR) could only be obtained recently. For more than forty years the process of designing new progestagens could therefore only be guided by the knowledge of the structure of the ligand and its corresponding in vitro/in vivo activities. While in early days chemical intuition and simple statistics (structure-activity relationship - SAR) were leading the drug design process, in later days more complex statistics and visualization tools have become routinely part of quantitative structure-activity relationship (QSAR) studies. The present review aims to provide a general overview of the strategies, efforts and achievements of synthetic and computational chemists in more than forty years of development of progestagens.

Comparative spectra analysis (CoSA): spectra as three-dimensional molecular descriptors for the prediction of biological activities.

A novel 3D QSAR approach, comparative spectra analysis (CoSA), in which molecular spectra are used as three-dimensional molecular descriptors for the prediction of biological activities, is presented and discussed. To this purpose, experimentally determined 1H NMR, mass, and IR spectra, as well as simulated IR and 13C NMR spectra, for a set of 45 diverse progestagens are converted by a program, SpecMat, into matrixes, which are subsequently employed in a multivariate regression analysis (PLS). The results are compared with those resulting from a comparative molecular field analysis (CoMFA). When used individually, spectral descriptors yield better correlations and predictions than molecular field descriptors. A combination of spectral descriptors with other descriptors, either spectral or molecular field in nature, leads in most cases to models that are statistically superior to the ones obtained by their corresponding individual spectral or molecular field descriptors.

Comparative molecular field analysis and energy interaction studies of thrombin-inhibitor complexes.

A Comparative Molecular Field Analysis (CoMFA) and an interaction energy-based method were applied on a database holding the 3D structures of 29 thrombin-inhibitor complexes. Several parameters were optimized in both methods in order to obtain the best correlation between theoretical and experimentally determined binding (Ki) data. CoMFA, which only uses the information of the inhibitors, performed best (r = 0.99, q2 = 0.46, N = 29) when HF 6-31G charges were used in combination with a pharmacophore-based alignment. Inclusion of hydrophobic fields did not lead to improvements. The interaction energy-based approach uses the information of the whole thrombin-inhibitor complex. A statistically significant correlation (r = 0.74, N = 14) could only be obtained for a subset of the database containing the high resolution structures. Geometry optimization of the ligand only in combination with downscaled electrostatics performed best.

Platelet alpha-granule release in chronic myeloproliferative disorders with thrombocytosis.

Platelet alpha-granule release in 22 patients affected by chronic myeloproliferative disorders with thrombocytosis and seven subjects with thrombocytosis secondary to splenectomy were studied. We found elevated beta-thromboglobulin (BTG) and platelet factor 4 (PF4) plasma levels in all patients. Intraplatelet content of BTG and PF4 was decreased in patients with idiopathic thrombocythaemia (IT) and idiopathic myelofibrosis (IMF). The BTG and PF4 results were also expressed as the ratio plasma BTG and PF4: whole blood platelet count. In patients with IT, BTG: whole blood platelet count ratio was low, conversely, the same ratio was high in patients with IMF. In conclusion, our results suggest the presence of an abnormal, BTG-deficient clone in IT and a peripheral platelet activation in IMF.