Notes

We elucidated crucial roles of the methylsulfonyl group of 2 in its interaction with the hERG channel and the GPR119 receptor, presumably as a hydrogen bond acceptor (HBA)
To remove the undesirable hERG inhibitory activity, a strategy was implemented to arrange an HBA on a less conformationally flexible framework at the indoline 5-position instead of the methylsulfonyl group. This successfully led to the discovery of a piperidinone ring as a desirable motif at the indoline 5-position, which could minimize hERG liability as shown by 24b. Further optimization focused on the reduction of lipophilicity in terms of more favorable drug-like properties. Consequently, the introduction of a hydroxy group at the 3-position of the piperidinone ring effectively reduced lipophilicity without compromising GPR119 potency, resulting in the identification of (3S)-3-hydroxy-1-1-[6-(1-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-4-yloxy)pyrimidin-4-yl]- 2,3-dihydro-1H-indol-5-ylpiperidin-2-one ((S)-29) as a novel, potent, and orally bioavailable GPR119 agonist with a well-balanced profile. The pharmacological effects of this compound were also confirmed after single and chronic oral administration in diabetic animal models.Glucagon-like peptide-1 and-2 levels in children with diabetic ketoacidosis.

OBJECTIVE: The aim of this study was to investigate whether insulin deficiency and increased catabolism may have a role in the regulation of plasma glucagon-like peptide (GLP)-1 and GLP-2 levels in children with diabetic ketoacidosis (DKA) and whether insulin treatment may affect the levels of these METHODS: Plasma GLP-1 and -2 levels were measured in 24 patients with DKA aged 8 to 14 years before insulin infusion (time 0), when ketonemia and acidosis disappeared (time 1), and when weight gain started (time 2). Eighteen healthy children aged 8 to 14 years constituted the control group.RESULTS: At time 0, mean plasma GLP-1 and GLP-2 levels were significantly elevated in the patients compared with the control group (p<05 and p<01, respectively). At time 1 when ketonemia and acidosis disappeared, GLP-1 and GLP-2 levels decreased significantly from the initial levels (p<05 and p<01, respectively). At this time, while GLP-1 level was not different from that of the controls, GLP-2 level was higher than that of the controls (p<05). GLP-1 and-2 levels did not show any significant differences between the patients and controls when weight gain started (time 2).CONCLUSION: Our results show that DKA is associated with increased plasma GLP-1 and -2 concentrations.

Effective fluid and insulin treatment resulted in a significant decrease in plasma GLP-1 and -2 levels. glucagon-like peptide 1 may be due to the negative feedback effect of insulin on the production of these polypeptides.Oxyntomodulin differentially affects glucagon-like peptide-1 receptor beta-arrestin recruitment and signaling through Galpha(s).The glucagon-like peptide (GLP)-1 receptor is a promising target for the treatment of type 2 diabetes and obesity, and there is great interest in characterizing the pharmacology of the GLP-1 receptor and its ligands. In the present report, we have applied bioluminescence resonance energy transfer assays to measure agonist-induced recruitment of betaarrestins and G-protein-coupled receptor kinase (GRK) 2 to the GLP-1 receptor in addition to traditional measurements of second messenger generation. The peptide hormone oxyntomodulin is described in the literature as a full agonist on the glucagon and GLP-1 receptors. Surprisingly, despite being full agonists in GLP-1 receptor-mediated cAMP accumulation, oxyntomodulin and glucagon were observed to be partial agonists in recruiting betaarrestins and GRK2 to the GLP-1 receptor.

We suggest that oxyntomodulin and glucagon are biased ligands on the GLP-1 receptor.[Role of exendin-4 in cardiovascular diseases].4595. Nihon Rinsho. 2012 May;70 Suppl 3:703-6.[Prospects for incretin-related drugs].Medicine, Kansai Electric Power Hospital.

Activation of Short and Long Chain Fatty Acid Sensing Machinery in the Ileum Toronto, Ontario M5G 1L7, the Departments of Physiology and.Toronto, Ontario M5G 1L7, the Departments of Physiology and Medicine, University of Toronto, Toronto, Ontario M5S 1A8, and the Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario M5G 2C4, Canada Evidence continues to emerge detailing the myriad of ways the gut microbiota influences host energy homeostasis. Among the potential mechanisms, short chain fatty acids (SCFAs), the byproducts of microbial fermentation of dietary fibers, exhibit correlative beneficial metabolic effects in humans and rodents, including improvements in glucose homeostasis. The underlying mechanisms, however, remain elusive. We here report that one of the main bacterially produced SCFAs, propionate, activates ileal mucosal free fatty acid receptor 2 to trigger a negative feedback pathway to lower hepatic glucose production in healthy rats in vivo We further demonstrate that an ileal glucagon-like peptide-1 receptor-dependent neuronal network is necessary for ileal propionate and long chain fatty acid sensing to regulate glucose homeostasis. These findings highlight the potential to manipulate fatty acid sensing machinery in the ileum to regulate glucose homeostasis.10016/j.

bbrc015408. Epub 2015 Apr 11.
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