Regulation of Endogenous (Male) Rodent GLP-1 Secretion and Human Islet Insulin Secretion by Antagonism of Somatostatin Receptor 5.

Incretin and insulin responses to nutrient loads are suppressed in persons with diabetes, resulting in decreased glycemic control. Agents including sulfonylureas and dipeptidyl peptidase-4 inhibitors (DPP4i) partially reverse these effects and provide therapeutic benefit; however, their modes of action limit efficacy. Because somatostatin (SST) has been shown to suppress insulin and glucagonlike peptide-1 (GLP-1) secretion through the Gi-coupled SST receptor 5 (SSTR5) isoform in vitro, antagonism of SSTR5 may improve glycemic control via intervention in both pathways. Here, we show that a potent and selective SSTR5 antagonist reverses the blunting effects of SST on insulin secretion from isolated human islets, and demonstrate that SSTR5 antagonism affords increased levels of systemic GLP-1 in vivo. Knocking out Sstr5 in mice provided a similar increase in systemic GLP-1 levels, which were not increased further by treatment with the antagonist. Treatment of mice with the SSTR5 antagonist in combination with a DPP4i resulted in increases in systemic GLP-1 levels that were more than additive and resulted in greater glycemic control compared with either agent alone. In isolated human islets, the SSTR5 antagonist completely reversed the inhibitory effect of exogenous SST-14 on insulin secretion. Taken together, these data suggest that SSTR5 antagonism should increase circulating GLP-1 levels and stimulate insulin secretion (directly and via GLP-1) in humans, improving glycemic control in patients with diabetes.

Stereospecific synthesis of polyfunctionalized carbacephams induced by titanocene(III) chloride.

Enantiomerically pure N-substituted epoxyalkene-2-azetidinones reacted with titanocene monochloride to give stereospecifically polyfunctionalized bicyclic beta-lactams. Four isomeric epoxyaldehydes 2 reacted with TiCp2Cl to give exclusively the respective carbacephams 7 while under the same reaction conditions the epoxyesters 1, which are more hindered for an intramolecular addition, gave the cyclization products 6 (only two isomers) and/or the elimination products 5 (all isomers).

Stereospecific synthesis of highly functionalized tricyclic beta-lactams by radical cyclizations using titanocene monochloride.

The reductive opening of epoxyimonobactams 1 with titanoncene (III) chloride gives rise to radicals that can be trapped by intramolecular pi systems (i.e., conjugated alkenes and lactone and amide carbonyls) in a stereospecific way to give new carbocyclic compounds such as tribactam 2.