Target 2035 - an update on private sector contributions.

Target 2035, an international federation of biomedical scientists from the public and private sectors, is leveraging 'open' principles to develop a pharmacological tool for every human protein. These tools are important reagents for scientists studying human health and disease and will facilitate the development of new medicines. It is therefore not surprising that pharmaceutical companies are joining Target 2035, contributing both knowledge and reagents to study novel proteins. Here, we present a brief progress update on Target 2035 and highlight some of industry's contributions.

BAY-7081: A Potent, Selective, and Orally Bioavailable Cyanopyridone-Based PDE9A Inhibitor.

Despite advances in the treatment of heart failure in recent years, options for patients are still limited and the disease is associated with considerable morbidity and mortality. Modulating cyclic guanosine monophosphate levels within the natriuretic peptide signaling pathway by inhibiting PDE9A has been associated with beneficial effects in preclinical heart failure models. We herein report the identification of BAY-7081, a potent, selective, and orally bioavailable PDE9A inhibitor with very good aqueous solubility starting from a high-throughput screening hit. Key aspect of the optimization was a switch in metabolism of our lead structures from glucuronidation to oxidation. The switch proved being essential for the identification of compounds with improved pharmacokinetic profiles. By studying a tool compound in a transverse aortic constriction mouse model, we were able to substantiate the relevance of PDE9A inhibition in heart diseases.

Target 2035 - update on the quest for a probe for every protein.

Twenty years after the publication of the first draft of the human genome, our knowledge of the human proteome is still fragmented. The challenge of translating the wealth of new knowledge from genomics into new medicines is that proteins, and not genes, are the primary executers of biological function. Therefore, much of how biology works in health and disease must be understood through the lens of protein function. Accordingly, a subset of human proteins has been at the heart of research interests of scientists over the centuries, and we have accumulated varying degrees of knowledge about approximately 65% of the human proteome. Nevertheless, a large proportion of proteins in the human proteome (∼35%) remains uncharacterized, and less than 5% of the human proteome has been successfully targeted for drug discovery. This highlights the profound disconnect between our abilities to obtain genetic information and subsequent development of effective medicines. Target 2035 is an international federation of biomedical scientists from the public and private sectors, which aims to address this gap by developing and applying new technologies to create by year 2035 chemogenomic libraries, chemical probes, and/or biological probes for the entire human proteome.

xMaP-An Interpretable Alignment-Free Four-Dimensional Quantitative Structure-Activity Relationship Technique Based on Molecular Surface Properties and Conformer Ensembles.

A novel alignment-free molecular descriptor called xMaP (flexible MaP descriptor) is introduced. The descriptor is the advancement of the previously published translationally and rotationally invariant three-dimensional (3D) descriptor MaP (mapping property distributions onto the molecular surface) to the fourth dimension (4D). In addition to MaP, xMaP is independent of the chosen starting conformation of the encoded molecules and is therefore entirely alignment-free. This is achieved by using ensembles of conformers, which are generated by conformational searches. This step of the procedure is similar to Hopfinger's 4D quantitative structure-activity relationship (QSAR). A five-step procedure is used to compute the xMaP descriptor. First, a conformational search for each molecule is carried out. Next, for each of the conformers an approximation to the molecular surface with equally distributed surface points is computed. Third, molecular properties are projected onto this surface. Fourth, areas of identical properties are clustered to so-called patches. Fifth, the spatial distribution of the patches is converted into an alignment-free descriptor that is based on the entire conformer ensemble. The resulting descriptor can be interpreted by superimposing the most important descriptor variables and the molecules of the data set. The most important descriptor variables are identified with chemometric regression tools. The novel descriptor was applied to several benchmark data sets and was compared to other descriptors and QSAR techniques comprising a binary fingerprint, a topological pharmacophore descriptor (Cats2D), and the field-based 3D-QSAR technique GRID/PLS which is alignment-dependent. The use of conformer ensembles renders xMaP very robust. It turns out that xMaP performs very well on (almost) all data sets and that the statistical results are comparable to GRID/PLS. In addition to that, xMaP can also be used to efficiently visualize the derived quantitative structure-activity relationships.

Neurocognitive functioning in parents of schizophrenia patients: Attentional and executive performance vary with genetic loading.

Neuropsychological deficits are candidate endophenotypes of schizophrenia which can assist to explain the neurocognitive impact of genetic risk variants. The identification of endophenotypes is often based on the familiality of these phenotypes. Several studies demonstrate neuropsychological deficits in unaffected biological relatives of schizophrenia patients without differentiating between genetic and non-genetic factors underlying these deficits. We assessed N=129 unaffected biological parents of schizophrenia patients, N=28 schizophrenia patients (paranoid subtype), and N=143 controls without a family history of schizophrenia with an extensive neuropsychological test battery. Direct comparison of N=22 parents with an ancestral history of schizophrenia (more likely carriers, MLC) and N=17 of their spouses without such a history (less likely carriers, LLC) allowed the separation of genetic and non-genetic aspects in cognition. Overall, parents showed significant deficits in neuropsychological tasks from all cognitive domains with medium effect sizes. Direct comparisons of MLC- and LLC-parents showed that attentional and executive tasks were most strongly affected by genetic loading. To conclude, unaffected parents of schizophrenia patients showed modest yet significant impairments in attention, memory, and executive functioning. In particular, attentional and executive impairments varied most strongly with genetic loading for schizophrenia, prioritising these dysfunctions for genotype-endophenotype analyses.

2-Anilino-4-(benzimidazol-2-yl)pyrimidines--a multikinase inhibitor scaffold with antiproliferative activity toward cancer cell lines.

2-Anilino-4-(benzimidazol-2-yl)-pyrimidines, synthesized by reaction of a readily available benzimidazole-substituted enaminone with suitable arylguanidines, were shown to inhibit four cancer-related protein kinases (Aurora B, PLK1, FAK, and VEGF-R2). The most potent derivative exhibited antiproliferative activity for several cancer cell lines of the NCI in vitro cell line panel in submicromolar concentrations. Both the anilinopyrimidine structure and the substitution pattern at the aniline ring appear to be important for the protein kinase inhibitory activity.

QSAR guided synthesis of simplified antiplasmodial analogs of naphthylisoquinoline alkaloids.

Naphthylisoquinoline alkaloids have attracted considerable interest because of their intriguing structure, their unique biosynthetic origin, and their biological activities against several pathogens causing tropical diseases. Their promising pharmacologic properties make them suitable lead structures for new agents, in particular against malaria. Since these natural products are not easy to isolate in sufficient quantities or to synthesize stereoselectively, quantitative structure-activity relationship studies were accomplished to find new antiplasmodial analogs that are structurally related to the naturally occurring naphthylisoquinoline alkaloids, but more easily accessible, more active against Plasmodium falciparum, and, last but not least, less toxic. We report on the synthesis of several simplified compounds by a Suzuki coupling between the naphthalene and the isoquinoline moieties and on their activities against different pathogens causing infectious diseases. Some structures were found to exhibit excellent--and selective--activities against P. falciparum in vitro.

Identification of 2-anilino-9-methoxy-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-ones as dual PLK1/VEGF-R2 kinase inhibitor chemotypes by structure-based lead generation.

To develop multikinase inhibitors with dual PLK1/VEGF-R2 inhibitory activity, the d-annulated 1-benzazepin-2-one scaffold present in the paullone family of kinase inhibitors was investigated as a general structure template suitable for anchoring annulated heterocycles at the hinge region of the ATP binding site. For this purpose, the indole substructure of the paullones was replaced by other nitrogen containing heteroaromatics. The designed scaffolds were synthesized and tested on the indicated kinases. The 2-anilino-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-ones were found to be VEGF-R2 inhibitors with selectivity against the insulin receptor kinase. The attachment of a methoxy group to the 9-position of the scaffold led to additional PLK1 inhibitory activity, which was explained by an alternative binding mode of the 9-methoxy derivatives. Selected members of the compound class inhibited the VEGF-R2 autophosphorylation in human umbilical vein endothelial cells, the sprouting of human umbilical vein endothelial cell speroids, and the proliferation of diverse cancer cell lines.

[Aggressive behaviour and substance abuse among schizophrenic adolescents compared to antisocial adolescents--a follow-up study]. / Aggressives Verhalten und Substanzmittelkonsum bei an Schizophrenie erkrankten Jugendlichen im Vergleich zu dissozialen Jugendlichen, eine follow-up Studie.

OBJECTIVES: The objective of this study was to analyze aggressive behaviour towards others by schizophrenic as opposed to antisocial adolescents, and the influence of substance abuse before, during and after their hospitalization. METHODS: We analyzed 21 schizophrenic adolescents and compared their aggressive behaviour and their substance abuse to that of 21 antisocial juveniles before and during their hospitalization and again at the time of a follow-up interview. The two samples were matched for age, sex and intelligence. In a first step, data were gathered from the hospital records, in a second step, for follow-up data we conducted standardized telephone interview with the patient and his or her parent or caregiver. Within the analysis we focused on aggressive behaviour towards other people and objects, as well as on criminal acts and regular substance abuse. RESULTS: We found less aggressive behaviour among psychotic patients during and post-hospitalization than among their antisocial counterparts. As inpatients, the acutely psychotic juveniles were at higher risk for aggressive acts, but adequate treatment subdued their offensive behaviour. In the long term, there were fewer criminal arrests among psychotic patients. Only in connection with their substance abuse, their aggressive misconduct towards others increased. CONCLUSIONS: Our results suggest that drug treatment during adolescence might help to lessen the risk of aggressive behaviour towards others.

Infanticide in female forensic patients: the view from the evolutionary standpoint.

Evolutionary theory predicts that very young mothers would be more likely to kill an infant than older women, given that the younger mother has a much greater ability to "replace" the dead child through subsequent pregnancies and thus to produce offspring for the next generation. Evolutionary theory also predicts that a woman would be more likely to kill a child if the child was obviously defective, the pregnancy was the result of incest or rape, or if the mother's means of supporting the child were severely compromised. The authors hypothesized that mentally ill mothers would behave in a way that differed significantly from evolutionary expectations, i.e., that they would be more likely to kill children who were older than those killed by mothers in the general population and that the mothers themselves would be likely to be older than mothers in the general population when the murders occurred. To test this hypothesis, the authors compared infanticides (both filicides and neonaticides) committed by mentally ill mothers with those committed by mothers in the general population. They examined two samples: 1) all cases of maternal infanticide from the Mid-Hudson Forensic Psychiatric Hospital from 1978 (when the hospital began admitting female patients) through the year 2000 and 2) a general population sample from a 10-year Canadian study reported by Daly and Wilson in 1998. The authors focused on the following variables: ages of the mothers, ages of the child-victims, whether the pregnancy was the result of rape or incest, whether the child had significant behavioral or physical problems, and whether there were problems supporting the child (e.g., having no partner, poverty, mother's lack of education). The results of the analyses supported the authors' hypothesis about ages of mothers and children. The mentally ill mothers in the Mid-Hudson sample were generally older when they killed their children and the children who were killed were generally older than in the Daly and Wilson general population sample (where the majority of the cases involved neonaticide and the mothers were generally younger than 25 years of age). The three factors, poverty, low education level (or low intellectual capacity), and lack of a spouse were common in both samples. Findings concerning cultural factors, motives, and methods used will be presented in separate publications.