Publications by authors named "Finke P"

A series of structurally diverse azaspirodecanone and spirooxazolidinone analogues were designed and synthesized as potent and selective somatostatin receptor subtype 5 (SSTR5) antagonists. Four optimized compounds each representing a subseries showed improvement in their metabolic stability and pharmacokinetic profiles compared to those of the original lead compound while maintaining pharmacodynamic efficacy. The optimized cyclopropyl analogue demonstrated efficacy in a mouse oral glucose tolerance test and an improved metabolic profile and pharmacokinetic properties in rhesus monkey studies.

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Soil organic carbon (OC) sequestration (i.e. the capture and long-term storage of atmospheric CO) is being considered as a possible solution to mitigate climate change, notably through land use change (conversion of cropped land into pasture) and conservation agricultural practices (reduced tillage).

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To protect soils against threats, it is necessary to predict the consequences of human activities and global change on their evolution on a ten to hundred year time scale. Mechanistic modelling of soil evolution is then a useful tool. We analysed the ability of the SoilGen model to be used for projections of soil characteristics associated to various soil threats: vertical distributions of <2μm fraction, organic carbon content (OC), bulk density and pH.

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One-electron oxidation of two series of diaryldichalcogenides (CFE) () and (2,6-MesCHE) () was studied (E = S, Se, Te). The reaction of and with AsF and SbF gave rise to the formation of thermally unstable radical cations [(CFS)]˙ () and [(CFSe)]˙ () that were isolated as [SbF] and [AsF] salts, respectively. The reaction of with AsF afforded only the product of a Te-C bond cleavage, namely the previously known dication [Te] that was isolated as [AsF] salt.

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The reaction of the intramolecularly coordinated diaryltellurium(IV) oxide (8-Me2NC10H6)2TeO with acetonitrile proceeds with oxygen transfer and gives rise to the formation of the novel zwitterionic diaryltelluronium(IV) acetimidate (8-Me2NC10H6)2TeNC(O)CH3 (1) in 57% yield. Hydrolysis of 1 with hydrochloric acid affords acetamide and the previously known diarylhydroxytelluronium(IV) chloride [(8-Me2NC10H6)2Te(OH)]Cl.

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The stoichiometrically controlled halogenation of the intramolecularly coordinated diaryltelluride (8-Me2NC10H6)2Te using SO2Cl2, Br2 and I2 was studied. At an equimolar ratio, the diarylhalotelluronium cations [(8-Me2NC10H6)2TeX](+) (1, X = Cl; 2, X = Br; 3, X = I) formed and were isolated as 1·Cl(-)·H2O·1/2THF, 2·Br(-), and 3·I(-), respectively. When the same reactions were carried out in the presence of KPF6, 1·PF6(-) and 22·Br(-)·PF6(-) were obtained.

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The homoleptic 1:1 Lewis pair (LP) complex [MesTe(TeMes2)]O3SCF3 (1) featuring the cation [MesTe(TeMes2)](+) (1a) was obtained by the reaction of Mes2Te with HO3SCF3. The reaction of 1 with Ph3E (E = P, As, Sb, Bi) proceeded with substitution of Mes2Te and provided the heteroleptic 1:1 LP complexes [MesTe(EPh3)]O3SCF3 (2, E = P; 3, E = As) and [MesTe(SbPh3)][Ph2Sb(O3SCF3)2] (4) featuring the cations [MesTe(EPh3)](+) (2a, E = P; 3a, E = As; 4a, E = Sb) and the anion [Ph2Sb(O3SCF3)2](-) (4b). In the reaction with Ph3Bi, the crude product contained the cation [MesTe(BiPh3)](+) (5a) and the anion [Ph2Bi(O3SCF3)2](-) (5b); however, the heteroleptic 1:1 LP complex [MesTe(BiPh3)][Ph2Bi(O3SCF3)2] (5) could not be isolated because of its limited stability.

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Article Synopsis
  • The study investigates the development of Spasmolytic polypeptide-expressing metaplasia (SPEM) in mice and humans, focusing on parietal cell loss and its implications as a preneoplastic lesion.
  • Differences in RNA transcript patterns among SPEM from various mouse models were analyzed using gene microarrays and validated with PCR, highlighting key proteins like clusterin and CFTR.
  • Results showed that clusterin is consistently upregulated in all SPEM lineages and links to poor survival in gastric cancer, while CFTR expression is specific to inflamed SPEM, suggesting a progression towards a more intestinal-like metaplastic phenotype in inflamed conditions.
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Objective: Metaplastic lineages in the oxyntic mucosa of the stomach are critical preneoplastic precursors of gastric cancer. Recent studies have demonstrated that spasmolytic polypeptide-expressing metaplasia (SPEM) in the mouse oxyntic mucosa arises from transdifferentiation of mature gastric chief cells. Other investigations of intestinal progenitor cells have shown that cells demonstrating transcriptional activity for leucine-rich repeat containing G-protein-coupled receptor 5 (Lgr5) in the intestine, colon and gastric antrum function as adult stem cells.

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Background: Alpha-1-antitrypsin (A1AT) deficiency is the only recognised genetic risk factor for chronic obstructive pulmonary disease (COPD), a leading cause of morbidity and mortality worldwide. Since A1AT is the major inhibitor of neutrophil elastase (NE), this enzyme has become widely implicated in the pathogenesis of COPD in general; however, there is currently no specific biomarker for its pre-inhibition activity. Such a biomarker should be a measure of elastase-specific COPD disease activity with the potential to assess early targeted therapeutic intervention, in contrast to traditional and non-specific disease severity markers such as forced expiratory volume in 1 s.

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Article Synopsis
  • Gastric cancer develops in an abnormal stomach lining where parietal cells are lost, and mucous cells undergo changes, with mucous cell metaplasia being a significant precursor for cancer.
  • Research shows that SPEM, a type of metaplasia, arises from chief cells, especially when the stomach lining is damaged or inflamed through specific treatments or infections.
  • The study confirms that mature chief cells can revert back to a more primitive, proliferative state under inflammatory conditions, suggesting they can contribute to the development of SPEM and potentially gastric cancer.
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Article Synopsis
  • This study investigates if a mother's report of her child's behavior in early infancy can predict behavioral inhibition when the child is 14 months old.
  • A sample of 101 mother-infant pairs participated, with assessments of infant behavior conducted using the Infant Behaviour Questionnaire at 4 months and a lab measure at 14 months.
  • Results indicate that greater infant distress to novelty at 4 months is linked to higher behavioral inhibition at 14 months, suggesting that maternal observations can help identify infants at risk for anxiety disorders later in childhood.
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Background: Dissociation has been recognized as a relevant factor within the context of traumatization. Since childhood maltreatment as well as child birth can be regarded as a potential trauma, this study examined dissociation in a sample of 58 young mothers with a history of abuse in comparison to a control group.

Methods: All women with newborn children were contacted by mail and presented with the Childhood Trauma Questionnaire.

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Background: As a proposed risk factor for infant and child development, maternal history of abuse has been a frequent target of investigation. However, there have been no controlled studies about the impact of maternal history of abuse on the medical course of pregnancy, the peri- and postnatal period.

Method: All women with a newborn child were contacted by mail and presented with the Childhood Trauma Questionnaire (CTQ).

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We document in vitro and in vivo effects of a novel, selective cannabinoid CB(1) receptor inverse agonist, Imidazole 24b (5-(4-chlorophenyl)-N-cyclohexyl-4-(2,4-dichlorophenyl)-1-methyl-imidazole-2-carboxamide). The in vitro binding affinity of Imidazole 24b for recombinant human and rat CB(1) receptor is 4 and 10 nM, respectively. Imidazole 24b binds to human cannabinoid CB(2) receptor with an affinity of 297 nM; in vitro, it is a receptor inverse agonist at both cannabinoid CB(1) and CB(2) receptors as it causes a further increase of forskolin-induced cAMP increase.

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The synthesis and optimization of a cyclopentane-based hNK1 antagonist scaffold 3, having four chiral centers, will be discussed in the context of its enhanced water solubility properties relative to the marketed anti-emetic hNK1 antagonist EMEND (Aprepitant). Sub-nanomolar hNK1 binding was achieved and oral activity comparable to Aprepitant in two in vivo models will be described.

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An initial investigation of the novel cyclopentane scaffold 6 afforded low nanomolar human NK1 antagonists having enhanced water solubility properties compared to morpholine 1. A synthesis of this cyclopentane scaffold, having three contiguous chiral centers, and the unexpected determination that the 1,2-trans-2,3-trans-ring stereochemistry, as opposed to the cis-ether/phenyl configuration of the known structures 1-5, is optimal for this class of antagonist are described.

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Structure-activity relationship studies directed toward the optimization of 4,5-diarylimidazole-2-carboxamide analogs as human CB1 receptor inverse agonists resulted in the discovery of the two amide derivatives 24a and b (hCB1 IC50 = 6.1 and 4.0 nM) which also demonstrated efficacy in overnight feeding studies in the rat for reduction in both food intake and overall body weight.

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Structure-activity relationship studies for two series of 2-benzyloxy-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyridines having either a 3-cyano or 3-carboxamide moiety resulted in the preparation of the 2-(3,4-difluorobenzyloxy)-3-nitrile analog 10d and the 2-(3,4-difluorobenzyloxy)-3-(N-propylcarboxamide) analog 16c, (hCB1 IC(50)=1.3 and 1.7 nM, respectively) as potent and selective hCB1 inverse agonists.

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Cellular proliferation of HIV-1 requires the cooperative assistance of both the CCR5 and CD4 receptors. Our medicinal chemistry efforts in this area have resulted in the identification of N-alkyl piperidine sulfones as CCR5 antagonists. These compounds display potent binding and show antiviral properties in HIV-1 spread cell-based assays.

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The absorption, metabolism, and excretion of [14C]aprepitant, a potent and selective human substance P receptor antagonist for the treatment of chemotherapy-induced nausea and vomiting, was evaluated in rats and dogs. Aprepitant was metabolized extensively and no parent drug was detected in the urine of either species. The elimination of drug-related radioactivity, after i.

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[reaction: see text] A novel approach to alpha,alpha-disubstituted-beta-amino acids (beta(2,2)-amino acids) was employed in the synthesis of a series of 3-(pyrrolidin-1-yl)propionic acids possessing high affinity for the CCR5 receptor and potent anti-HIV activity. The rat pharmacokinetics for these new analogues featured higher bioavailabilities and lower rates of clearance as compared to cyclopentane 1.

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