ABSTRACT
We have used a previously unavailable model of pancreatic development, derived in vitro from human embryonic stem cells, to capture a time-course of gene, miRNA and histone modification levels in pancreatic endocrine cells. We investigated whether it is possible to better understand, and hence control, the biological pathways leading to pancreatic endocrine formation by analysing this information and combining it with the available scientific literature to generate models using a casual reasoning approach. We show that the embryonic stem cell differentiation protocol is highly reproducible in producing endocrine precursor cells and generates cells that recapitulate many aspects of human embryonic pancreas development, including maturation into functional endocrine cells when transplanted into recipient animals. The availability of whole genome gene and miRNA expression data from the early stages of human pancreatic development will be of great benefit to those in the fields of developmental biology and diabetes research. Our causal reasoning algorithm suggested the involvement of novel gene networks, such as NEUROG3/E2F1/KDM5B and SOCS3/STAT3/IL-6, in endocrine cell development We experimentally investigated the role of the top-ranked prediction by showing that addition of exogenous IL-6 could affect the expression of the endocrine progenitor genes NEUROG3 and NKX2.2.
Subject(s)
Cell Differentiation/genetics , Cell Lineage/genetics , Gene Regulatory Networks , Islets of Langerhans/metabolism , Algorithms , Animals , Gene Expression Profiling , Gene Expression Regulation, Developmental , Glucose Tolerance Test , Homeobox Protein Nkx-2.2 , Homeodomain Proteins , Humans , Insulin-Secreting Cells/cytology , Insulin-Secreting Cells/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Islets of Langerhans/embryology , Mice , Nuclear Proteins , Transcription FactorsABSTRACT
We describe the design, synthesis, and structure-activity relationships of triazolobenzodiazepinone CCK1 receptor agonists. Analogs in this series demonstrate potent agonist activity as measured by in vitro and in vivo assays for CCK1 agonism. Our efforts resulted in the identification of compound 4a which significantly reduced food intake with minimal systemic exposure in rodents.
Subject(s)
Anti-Obesity Agents/pharmacology , Benzodiazepines/pharmacology , Receptors, Cholecystokinin/agonists , Animals , Anti-Obesity Agents/pharmacokinetics , Benzodiazepines/chemistry , Benzodiazepines/pharmacokinetics , Male , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
A novel series of heterocycle-based analogs were prepared and evaluated for their in vitro and in vivo biological activity as human beta(3)-adrenergic receptor (AR) agonists. Several analogs demonstrated potent agonist activity at the beta(3)-AR, functional selectivity against beta(1)- and beta(2)-ARs, and favorable pharmacokinetic profiles in vivo. Compound 17 increased oxygen consumption in rats, a measure of energy expenditure, with an ED(20%) of 2mg/kg.
Subject(s)
Adrenergic beta-3 Receptor Agonists , Adrenergic beta-Agonists/therapeutic use , Obesity/drug therapy , Administration, Oral , Adrenergic beta-Agonists/administration & dosage , Adrenergic beta-Agonists/pharmacokinetics , Adrenergic beta-Agonists/pharmacology , Animals , Biological Availability , RatsABSTRACT
A series of sulfamide-based analogs related to L-796568 were prepared and evaluated for their biological activity at the human beta(3)-adrenergic receptor (AR). This modification allows for a significant reduction in molecular weight, while maintaining single-digit nanomolar potencies at the beta(3)-AR and high selectivities versus the beta(2)- or beta(3)-AR.
