General Strategies.- Regression Models.- Classification Models.- Other Considerations.- Appendix.- References.- Indices.

Applied Predictive Modeling

The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated molecular construction that broadens biological mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.

Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design.

Molecular recognition in biological systems relies on the existence of specific attractive interactions between two partner molecules. Structure-based drug design seeks to identify and optimize such interactions between ligands and their host molecules, typically proteins, given their three-dimensional structures. This optimization process requires knowledge about interaction geometries and approximate affinity contributions of attractive interactions that can be gleaned from crystal structure and associated affinity data.

Here we compile and review the literature on molecular interactions as it pertains to medicinal chemistry through a combination of careful statistical analysis of the large body of publicly available X-ray structure data and experimental and theoretical studies of specific model systems. We attempt to extract key messages of practical value and complement references with our own searches of the CSDa,(1) and PDB databases.(2) The focus is on direct contacts between ligand and protein functional groups, and we restrict ourselves to those interactions that are most frequent in medicinal chemistry applications. Examples from supramolecular chemistry and quantum mechanical or molecular mechanics calculations are cited where they illustrate a specific point. The application of automated design processes is not covered nor is design of physicochemical properties of molecules such as permeability or solubility.

Throughout this article, we wish to raise the readers’ awareness that formulating rules for molecular interactions is only possible within certain boundaries. The combination of 3D structure analysis with binding free energies does not yield a complete understanding of the energetic contributions of individual interactions. The reasons for this are widely known but not always fully appreciated. While it would be desirable to associate observed interactions with energy terms, we have to accept that molecular interactions behave in a highly nonadditive fashion.3,4 The same interaction may be worth different amounts of free energy in different contexts, and it is very hard to find an objective frame of reference for an interaction, since any change of a molecular structure will have multiple effects. One can easily fall victim to confirmation bias, focusing on what one has observed before and building causal relationships on too few observations. In reality, the multiplicity of interactions present in a single protein−ligand complex is a compromise of attractive and repulsive interactions that is almost impossible to deconvolute. By focusing on observed interactions, one neglects a large part of the thermodynamic cycle represented by a binding free energy: solvation processes, long-range interactions, conformational changes. Also, crystal structure coordinates give misleadingly static views of interactions. In reality a macromolecular complex is not characterized by a single structure but by an ensemble of structures. Changes in the degrees of freedom of both partners during the binding event have a large impact on binding free energy.

The text is organized in the following way. The first section treats general aspects of molecular design: enthalpic and entropic components of binding free energy, flexibility, solvation, and the treatment of individual water molecules, as well as repulsive interactions. The second half of the article is devoted to specific types of interactions, beginning with hydrogen bonds, moving on to weaker polar interactions, and ending with lipophilic interactions between aliphatic and aromatic systems. We show many examples of structure−activity relationships; these are meant as helpful illustrations but individually can never confirm a rule.

http://pubs.acs.org/doi/pdf/10.1021/jm100112j

A Medicinal Chemist’s Guide to Molecular Interactions

Drug-likeness is a key consideration when selecting compounds during the early stages of drug discovery. However, evaluation of drug-likeness in absolute terms does not reflect adequately the whole spectrum of compound quality. More worryingly, widely used rules may inadvertently foster undesirable molecular property inflation as they permit the encroachment of rule-compliant compounds towards their boundaries. We propose a measure of drug-likeness based on the concept of desirability called the quantitative estimate of drug-likeness (QED). The empirical rationale of QED reflects the underlying distribution of molecular properties. QED is intuitive, transparent, straightforward to implement in many practical settings and allows compounds to be ranked by their relative merit. We extended the utility of QED by applying it to the problem of molecular target druggability assessment by prioritizing a large set of published bioactive compounds. The measure may also capture the abstract notion of aesthetics in medicinal chemistry.

/pdf/quantifying-the-chemical-beauty-of-drugs-48hax4bgv8.pdf

Quantifying the chemical beauty of drugs

Alzheimer's disease is the most common cause of dementia in elderly people. Research into Alzheimer's disease therapy has been at least partly successful in terms of developing symptomatic treatments, but has also had several failures in terms of developing disease-modifying therapies. These successes and failures have led to debate about the potential deficiencies in our understanding of the pathogenesis of Alzheimer's disease and potential pitfalls in diagnosis, choice of therapeutic targets, development of drug candidates, and design of clinical trials. Many clinical and experimental studies are ongoing, but we need to acknowledge that a single cure for Alzheimer's disease is unlikely to be found and that the approach to drug development for this disorder needs to be reconsidered. Preclinical research is constantly providing us with new information on pieces of the complex Alzheimer's disease puzzle, and an analysis of this information might reveal patterns of pharmacological interactions instead of single potential drug targets. Several promising randomised controlled trials are ongoing, and the increased collaboration between pharmaceutical companies, basic researchers, and clinical researchers has the potential to bring us closer to developing an optimum pharmaceutical approach for the treatment of Alzheimer's disease.

/pdf/alzheimer-s-disease-clinical-trials-and-drug-development-46wp4j0jf2.pdf

Alzheimer's disease: clinical trials and drug development

L'invention concerne des composes et des sels pharmaceutiquement acceptables de ces composes, les composes presentant la structure de formule (I), dans laquelle X, R 1 , R 2a , R 2b , R 4a , R 4b , R 5a , R 5b , R 6 , R 7 R 10 , R 11 , et y sont tels que definis dans la description. L'invention concerne egalement des compositions pharmaceutiques, des methodes de traitement, des procedes de synthese et des produits intermediaires correspondants.

Nouveaux pyridopyrazinediones cyclopropabenzofuranyl

The present invention is directed to a new class of triazine derivatives as described by formula I below in which A, X, R, R, R, and Rare as defined herein and to the use of the compounds as phosphodiesterase 10 (PDE10) inhibitors.

Imidazo-triazine derivatives as inhibitors of phosphodiesterase 10 (pde10)

The present invention is directed to compounds, tautomers and pharmaceutically acceptable salts of the compounds which are disclosed, wherein the compounds have the structure of Formula I, wherein the variables R1, R2 and R3 are as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

N-[2-(3-amino-2,5-dimethyl-1,1-dioxido-5,6-dihydro-2H-1,2,4-thiadiazin-5-yl)-1,3-thiazol-4-yl] amides

L'invention porte sur des composes inhibant PDE9 de Formule (I) et sur des sels pharmaceutiquement acceptables de ceux-ci, ou R, R1, R2 et R3 sont tels que definis presentement. L'invention porte egalement sur des compositions pharmaceutiques contenant les composes de Formule I et sur les utilisations de celles-ci dans le traitement de troubles neurodegeneratifs et cognitifs, tels que la maladie d'Alzheimer et la schizophrenie.

Composés amino-hétérocycliques

La presente invention concerne des composes 3-amino-1-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline-7-carbonitrile, 3-amino-1-hydroxy-7-(2- methoxyethoxy)-3,4-dihydroquinolin-2(1H)-one, et 3-amino-1-hydroxy-7-[(1S)-2-methoxy-1-methylethoxy]-3,4-dihydroquinolin-2(1H)-one, y compris leurs melanges racemiques et leurs enantiomeres resolus, leurs sels pharmaceutiquement acceptables, et le traitement de deficits cognitifs associes a la schizophrenie et d'autres troubles psychiatriques, neurodegeneratifs et/ou neurologiques chez des mammiferes, y compris chez l'etre l'humain

Patrick Robert Verhoest

Papers

Nouveaux pyridopyrazinediones cyclopropabenzofuranyl

Imidazo-triazine derivatives as inhibitors of phosphodiesterase 10 (pde10)

N-[2-(3-amino-2,5-dimethyl-1,1-dioxido-5,6-dihydro-2H-1,2,4-thiadiazin-5-yl)-1,3-thiazol-4-yl] amides

Composés amino-hétérocycliques

Inhibiteurs de kat ii