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Sackus A.,Kaunas University of Technology | Brickute D.,Kaunas University of Technology | Paliulis O.,Kaunas University of Technology | Slok F.A.,Vipergen ApS
Journal of Heterocyclic Chemistry | Year: 2015

A method for the preparation of heterocyclic analogs of α-aminoadipic acid and its esters based on the imidazo[2,1-b][1,3]thiazole ring system was developed. In this method, free-radical bromination of ethyl 6-methylimidazo[2,1-b][1,3]thiazole-5-carboxylate with NBS afforded a versatile building block, ethyl 6-bromomethylimidazo[2,1-b][1,3]thiazole-5-carboxylate. Coupling of ethyl 6-bromomethylimidazo[2,1-b][1,3]thiazole-5-carboxylate with Schöllkopf's chiral auxiliary followed by acidic hydrolysis generated ethyl 6-[(2S)-2-amino-3-methoxy-3-oxopropyl]imidazo[2,1-b][1,3]thiazole-5-carboxylate. A similar procedure using diethyl (Boc-amino)malonate yielded racemic 2-amino-3-[(5-ethoxycarbonyl)imidazo[2,1-b][1,3]thiazol-6-yl]propanoic acid. © 2014 HeteroCorporation.

Paulsen S.J.,Gubra | Larsen L.K.,Vipergen ApS | Hansen G.,Gubra | Chelur S.,Aurigene Discovery Technologies Ltd | And 2 more authors.
PLoS ONE | Year: 2014

Stimulation of the G protein coupled receptor GPR120 has been shown to have anti-inflammatory and insulin-sensitizing effects, to promote glucagon like peptide-1 (GLP-1) secretion, and to play a key role in sensing dietary fat and control energy balance. In a search for differentially expressed genes potentially involved in food intake and body-weight regulation we identified GPR120 to be differentially regulated in the intestine of selectively bred diet induced obese (DIO) and diet resistant (DR) rats. Subsequently we investigated the effect of GPR120 receptor stimulation with the long chain fatty acid alpha linolenic acid (ALA) on GLP-1 secretion in rats. Independent of diet (high or low fat), GPR120 expression showed a two-fold increase in the intestine of DIO compared to DR rats. In situ hybridization revealed a broad expression of GPR120 in the gut mucosa in both intestinal epithelial and endocrine cells. Using double in situ hybridization GPR120 mRNA did not appear to be enriched in preproglucagon expressing L-cells. In line with the anatomical data, ALA administration did not increase circulating GLP-1 levels. Our data shows a widespread expression of GPR120 in the gut epithelium and can not confirm a major role for GPR120 in the regulation of GLP-1 secretion. The broad expression of GPR120 in the gut epithelium supports reports indicating a putative role of GPR120 as a sensor of dietary fat. © 2014 Paulsen et al.

Albrechtsen A.,Copenhagen University | Grarup N.,Novo Nordisk AS | Li Y.,BGI Shenzhen | Sparso T.,Novo Nordisk AS | And 125 more authors.
Diabetologia | Year: 2013

Aims/hypothesis: Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. Methods: The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m2 and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case-control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. Results: Exome sequencing identified 70,182 polymorphisms with MAF >1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10-14), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10-11) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10-10). Conclusions/interpretation: We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits. © 2012 The Author(s).

Vipergen Aps | Date: 2012-05-17

Disclosed is a composition comprising the nucleic acid and a chemical compound, said composition forming a star structure defining 3 or more stems extending from a reaction center. The stems are formed by a nucleic acid duplex and the chemical compound has been formed in the reaction center as the reaction product of 3 or more chemical groups. The advantage of the composition is that a close proximity is provided between the chemical groups in the reaction center, thereby promoting a reaction. The invention also relates to a method for preparation of the composition. The advantage of the method is that it does not require the pre-synthesis of a large number of templates and that it is not dependent upon codon/anti-codon recognition for an encoded molecule to be formed.

Petersen L.K.,Vipergen ApS | Blakskjaer P.,Vipergen ApS | Chaikuad A.,University of Oxford | Christensen A.B.,Vipergen ApS | And 10 more authors.
MedChemComm | Year: 2016

A highly specific and potent (7 nM cellular IC50) inhibitor of p38α kinase was identified directly from a 12.6 million membered DNA-encoded small molecule library. This was achieved using the high fidelity yoctoReactor technology (yR) for preparing the DNA-encoded library, and a homogeneous screening technique-the binder trap enrichment technology (BTE). Although structurally atypical to other kinase blockers, this inhibitor was found by X-ray crystallography to interact with the ATP binding site and provide strong distortion of the P-loop. Remarkably, it assumed an alternative binding mode as it lacks key features of known kinase inhibitors such as typical hinge binding motifs. Interestingly, the inhibitor bound assuming a canonical type-II ('DFG-out') binding mode by forming hinge hydrogen bonds with the backbone, showed excellent shape complementarity, and formed a number of specific polar interactions. Moreover, the crystal structure showed, that although buried in the p38α active site, the original DNA attachment point of the compound was accessible through a channel created by the distorted P-loop conformation. This study demonstrates the usability of DNA-encoded library technologies for identifying novel chemical matter with alternative binding modes to provide a good starting point for drug development. This journal is © The Royal Society of Chemistry 2016.

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