GLP-1/glucagon receptor co-agonism for treatment of obesity

Over a relatively short period, obesity and type 2 diabetes have come to represent a large medical and economic burden to global societies. The epidemic rise in the prevalence of obesity has metabolic consequences and is paralleled by an increased occurrence of other diseases, such as diabetes, cancer and cardiovascular complications. Together, obesity and type 2 diabetes constitute one of the more preventable causes of premature death and the identification of novel, safe and effective anti-obesity drugs is of utmost importance. Pharmacological attempts to treat obesity have had limited success, with notable adverse effects, rendering bariatric surgery as the only current therapy for substantially improving body weight. Novel unimolecular, multifunctional peptides have emerged as one of the most promising medicinal approaches to enhance metabolic efficacy and restore normal body weight. In this review, we will mainly focus on the discovery and translational relevance of dual agonists that pharmacologically function at the receptors for glucagon and glucagon-like peptide-1. Such peptides have advanced to clinical evaluation and inspired the pursuit of multiple related approaches to achieving polypharmacy within single molecules.     

Discovery of phosphoric acid mono-{2-[(E/Z)-4-(3,3-dimethyl-butyrylamino)-3,5-difluoro-benzoylimino]-thiazol-3-ylmethyl} ester (Lu AA47070): a phosphonooxymethylene prodrug of a potent and selective hA(2A) receptor antagonist

The discovery and structure-activity relationship of a series of hA(2A) receptor antagonists is described. Compound 28 was selected from the series as a potent and selective compound and was shown to be efficacious in an in vivo model of Parkinson's disease. It had acceptable ADME properties; however, the low intrinsic solubility of this compound was limiting for its developability, because the oral bioavailability from dosing in suspension was significantly lower than the oral bioavailability from solution dosage. As a consequence, prodrugs of 28 were prepared with dramatically increased aqueous solubility. The prodrugs efficiently delivered 28 into systemic circulation, with no detectable levels of prodrug in plasma samples. From this investigation, we selected 32 (Lu AA47070), a phosphonooxymethylene prodrug of 28, as a drug candidate.     

Genome-wide high-density SNP linkage search for glioma susceptibility loci: results from the Gliogene Consortium

Gliomas, which generally have a poor prognosis, are the most common primary malignant brain tumors in adults. Recent genome-wide association studies have shown that inherited susceptibility plays a role in the development of glioma. Although first-degree relatives of patients exhibit a two-fold increased risk of glioma, the search for susceptibility loci in familial forms of the disease has been challenging because the disease is relatively rare, fatal, and heterogeneous, making it difficult to collect sufficient biosamples from families for statistical power. To address this challenge, the Genetic Epidemiology of Glioma International Consortium (Gliogene) was formed to collect DNA samples from families with two or more cases of histologically confirmed glioma. In this study, we present results obtained from 46 U.S. families in which multipoint linkage analyses were undertaken using nonparametric (model-free) methods. After removal of high linkage disequilibrium single-nucleotide polymorphism, we obtained a maximum nonparametric linkage score (NPL) of 3.39 (P = 0.0005) at 17q12-21.32 and the Z-score of 4.20 (P = 0.000007). To replicate our findings, we genotyped 29 independent U.S. families and obtained a maximum NPL score of 1.26 (P = 0.008) and the Z-score of 1.47 (P = 0.035). Accounting for the genetic heterogeneity using the ordered subset analysis approach, the combined analyses of 75 families resulted in a maximum NPL score of 3.81 (P = 0.00001). The genomic regions we have implicated in this study may offer novel insights into glioma susceptibility, focusing future work to identify genes that cause familial glioma.     

Critical discussion of social-cognitive factors in smoking initiation among adolescents

Social-cognitive models have often been used in research on prevention in adolescent populations, even though the models were designed to describe adult behavior. The aim of the study reported here was to examine critically and constructively the five social-cognitive factors in the 'attitude, social influence, self-efficacy' (ASE) model. Methods. The examination draws on the results of a qualitative follow-up study of smoking initiation based on semi-structured interviews and observations of 12 adolescents in two Danish school classes, grades 7 and 8. The qualitative study was conducted in connection with and sampled from a large quantitative study and the results of both studies are discussed. In the analyses, we explored the ASE constructs according to how they are described in the ASE theory. Furthermore, we examined contradictions and aspects which are not explained in the model and if relevant discussed these aspects using other theoretical frameworks. Results. The results showed that aspects other than those in the ASE model are also important. Smoking initiation was often situational and unplanned and was sometimes used in negotiating social relationships and identity. Furthermore, the social-cognitive models are based on the assumption that adolescents talk about smoking norms and have a high degree of individual reflexivity, which is not always characteristic of adolescent behavior. Conclusion. Applying theoretical models in health research should be a continuous process of both applying the model and discussing the theoretical assumptions of the model when applied to a specific sample. The results of the qualitative study provide some support for use of the ASE model, but the results also suggest that further studies are needed to explore how social-cognitive models can be expanded to be more comprehensive behavioral models.