N′,2-Diphenylquinoline-4-carbohydrazide based NK3 receptor antagonists

The development and maintenance of spatial patterns and the way they affect the dynamics of populations and ecosystems is a key issue in ecology. Since each individual and each species experiences the environment on a unique range of scales, it is vital to determine the spatial scales across which organisms interact with each other and the structuring influence of their environments, which can be achieved by analyzing species’ distribution patterns. Here, the spatial variation in the distribution of <i>Scrobicularia plana</i> is described for 4 intertidal areas along the species’ distributional range. Spatial autocorrelation correlograms based on Moran’s coefficient reveal that while the Trondheim (Norway) population was randomly distributed, at Minho (Portugal), the Westerschelde, and the Wadden Sea (both in The Netherlands) populations were aggregated. Patch diameter varied from 150 to 1250 m, in Minho and Westerschelde, respectively; while in the Wadden Sea, patches of 4 to 10 km were detected. Comparisons of spatial patterns with those of other co-occurring bivalve species (<i>Abra tenuis</i>, <i>Cerastoderma edule</i>, and <i>Macoma balthica</i>) revealed that <i>S. plana</i>’s distribution was generally patchier. The distribution of <i>S. plana</i> was correlated with sediment type at Westerschelde and Trondheim, but not Minho. The observed differences in distribution patterns and their correlation with environmental factors reveal that spatial patterns of <i>S. plana</i> are site-specific rather than species-specific

Stimulation of Glucose-Dependent Insulin Secretion by a Potent, Selective sst₃ Antagonist

This letter provides the first pharmacological proof of principle that the sst₃ receptor mediates glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. To enable these studies, we identified the selective sst₃ antagonist (1<i>R</i>,3<i>R</i>)-3-(5-phenyl-1<i>H</i>-imidazol-2-yl)-1-(tetrahydro-2<i>H</i>-pyran-4-yl)-2,3,4,9-tetrahydro-1<i>H</i>-β-carboline (<b>5a</b>), with improved ion channel selectivity and mouse pharmacokinetic properties as compared to previously described tetrahydro-β-carboline imidazole sst3 antagonists. We demonstrated that compound <b>5a</b> enhances GSIS in pancreatic β-cells and blocks glucose excursion induced by dextrose challenge in ipGTT and OGTT models in mice. Finally, we provided strong evidence that these effects are mechanism-based in an ipGTT study, showing reduction of glucose excursion in wild-type but not sst₃ knockout mice. Thus, we have shown that antagonism of sst₃ represents a new mechanism with potential in treating type 2 diabetes mellitus

Diamine Derivatives as Novel Small-Molecule, Potent, and Subtype-Selective Somatostatin SST3 Receptor Agonists

A novel class of small-molecule, highly potent, and subtype-selective somatostatin SST3 agonists was discovered through modification of a SST3 antagonist. As an example, (1<i>R</i>,2<i>S</i>)-<b>9</b> demonstrated not only potent in vitro SST3 agonist activity but also in vivo SST3 agonist activity in a mouse oral glucose tolerance test (OGTT). These agonists may be useful reagents for studying the physiological roles of the SST3 receptor and may potentially be useful as therapeutic agents

Investigation of Cardiovascular Effects of Tetrahydro-β-carboline sstr3 antagonists

Antagonism of somatostatin subtype receptor 3 (sstr3) has emerged as a potential treatment of Type 2 diabetes. Unfortunately, the development of our first preclinical candidate, MK-4256, was discontinued due to a dose-dependent QTc (QT interval corrected for heart rate) prolongation observed in a conscious cardiovascular (CV) dog model. As the fate of the entire program rested on resolving this issue, it was imperative to determine whether the observed QTc prolongation was associated with hERG channel (the protein encoded by the human Ether-à-go-go-Related Gene) binding or was mechanism-based as a result of antagonizing sstr3. We investigated a structural series containing carboxylic acids to reduce the putative hERG off-target activity. A key tool compound, <b>3A</b>, was identified from this SAR effort. As a potent sstr3 antagonist, <b>3A</b> was shown to reduce glucose excursion in a mouse oGTT assay. Consistent with its minimal hERG activity from in vitro assays, <b>3A</b> elicited little to no effect in an anesthetized, vagus-intact CV dog model at high plasma drug levels. These results afforded the critical conclusion that sstr3 antagonism is not responsible for the QTc effects and therefore cleared a path for the program to progress

Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes

The imidazolyl-tetrahydro-β-carboline class of sstr3 antagonists have demonstrated efficacy in a murine model of glucose excursion and may have potential as a treatment for type 2 diabetes. The first candidate in this class caused unacceptable QTc interval prolongation in oral, telemetrized cardiovascular (CV) dogs. Herein, we describe our efforts to identify an acceptable candidate without CV effects. These efforts resulted in the identification of (1<i>R</i>,3<i>R</i>)-3-(4-(5-fluoropyridin-2-yl)-1<i>H</i>-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3<i>H</i>-2-one-5-yl)-2,3,4,9-tetrahydro-1<i>H</i>-β-carboline (<b>17e</b>, MK-1421)

The Discovery of MK-4256, a Potent SSTR3 Antagonist as a Potential Treatment of Type 2 Diabetes

A structure–activity relationship study of the imidazolyl-β-tetrahydrocarboline series identified MK-4256 as a potent, selective SSTR3 antagonist, which demonstrated superior efficacy in a mouse oGTT model. MK-4256 reduced glucose excursion in a dose-dependent fashion with maximal efficacy achieved at doses as low as 0.03 mg/kg po. As compared with glipizide, MK-4256 showed a minimal hypoglycemia risk in mice