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

The present invention provides novel 4,5-disubstituted-7H-pyrrolo[2,3-d]pyrimidine derivatives of Formula I, and the pharmaceutically acceptable salts thereof wherein R1, R2, R3, R4 and R5 are as defined in the specification. The invention is also directed to pharmaceutical compositions comprising the compounds of formula I and to use of the compounds in the treatment of diseases associated with LRRK2, such as neurodegenerative diseases including Parkinson's disease or Alzheimer's disease, cancer, Crohn's disease or leprosy.

Substituted pyrrolo[2,3-d]pyrimidines as LRRK2 inhibitors

L'invention concerne des derives pyrrolo{2,3-d}pyrimidine, leur utilisation comme inhibiteurs de la Janus Kinase (JAK), des compositions pharmaceutiques contenant ces derives et leurs utilisations therapeutiques.

Dérivés de pyrrolo[2,3-d]pyrimidine utiles pour inhiber la janus kinase

La presente invention concerne des composes de formule (I) et leurs sels pharmaceutiquement acceptables, les substituants R 1 , R 3 , R 6 , R 7 , et b etant tels que definis dans la description. L'invention se rapporte egalement a des compositions pharmaceutiques comprenant lesdits composes, a des methodes de traitement utilisant ces composes et a des procedes de preparation desdits composes.

Composés d'imidazopyridazine

La presente invention concerne de nouveaux imidazo [4,5- c ] quinoleine et imidazo [4,5- c ] [1,5] naphtyridine derives de Formule (I), et les sels pharmaceutiquement acceptables de ceux-ci, ou R 1 , R 1a , R 1b , R 2 , R 4 , R 5 , R 6 , X et Z sont tels que definis dans la description. L'invention concerne egalement des compositions pharmaceutiques comprenant les composes de formule (I) et l'utilisation de ces composes dans le traitement d'affections associees au gene LRRK2, telles que les maladies neurodegeneratives, notamment la maladie de Parkinson ou la maladie d'Alzheimer, le cancer, la maladie de Crohn ou la lepre.

Nouveaux dérivés imidazo [4,5-c] quinoline et imidazo [4,5-c] [1,5] naphthyridine utilisés comme inhibiteurs de lrrk2

La presente invention concerne des composes, des tautomeres et des sels pharmaceutiquement acceptables des composes selon l'invention, lesdits composes ayant la structure de formule I, dans laquelle les variables R 1 , R 2 et R 3 sont tels que definis dans la description. L'invention concerne egalement des compositions pharmaceutiques, des procedes de traitement, des procedes de synthese et des intermediaires correspondants.

Patrick Robert Verhoest

Papers

Substituted pyrrolo[2,3-d]pyrimidines as LRRK2 inhibitors

Dérivés de pyrrolo[2,3-d]pyrimidine utiles pour inhiber la janus kinase

Composés d'imidazopyridazine

Nouveaux dérivés imidazo [4,5-c] quinoline et imidazo [4,5-c] [1,5] naphthyridine utilisés comme inhibiteurs de lrrk2

N-[2-(3-amino-2,5-diméthyl-1,1-dioxido-5,6-dihydro-2h-1,2,4-thiadiazin-5-yl)-1,3-thiazol-4-yl] amides utiles comme inhibiteurs de bace