Prospects for pharmacologic inhibition of hepatic glucose production.

Type 2 diabetes is a widespread disease where effective pharmacologic therapies can have a profound beneficial public health impact. Increased hepatic glucose production (HGP) is observed in diabetics and its moderation by currently available agents provides therapeutic benefits. This review describes the challenges associated with the discovery of small molecules that inhibit HGP. Gluconeogenesis, glycogenolysis, liver architecture, and hepatocyte composition are described to provide background information on hepatic function. Current methods of target validation for drug discovery, HGP measurement, diabetes animal models, as well as current drug therapies are covered. In the accompanying review article the new drug targets being probed to produce the next generation of therapies are described. Significant pharmaceutical and academic efforts to pharmacologically inhibit HGP has the opportunity to provide new therapeutics for type 2 diabetics.

Potential drug targets and progress towards pharmacologic inhibition of hepatic glucose production.

A number of therapeutic targets are currently under investigation for inhibition of hepatic glucose production with small molecules. Antagonists of the glucagon receptor, glycogen phosphorylase, 11-beta-hydroxysteroid dehydrogenase-1 and fructose 1,6-bisphosphatase are, or have been, under evaluation in human clinical trials. Other strategies, including glucocorticoid receptor antagonists and carnitine palmitoyltransferase inhibitors, are supported by proof of principle studies in man as well as rodents. Several potential targets including glucose-6-phosphatase, glucose-6-phosphatase translocase, glycogen synthase kinase-3, adenosine receptor 2B antagonists, phosphoenolpyruvate carboxykinase and pyruvate dehydrogenase kinase, have been validated by compounds that are effective in animal models. Other targets like PGC-1a and CREB have initial validation support but no medicinal chemistry has been reported.

3,5-Bis(trifluoromethyl)pyrazoles: a novel class of NFAT transcription factor regulator.

A series of bis(trifluoromethyl)pyrazoles (BTPs) has been found to be a novel inhibitor of cytokine production. Identified initially as inhibitors of IL-2 synthesis, the BTPs have been optimized in this regard and even inhibit IL-2 production with a 10-fold enhancement over cyclosporine in an ex vivo assay. Additionally, the BTPs show inhibition of IL-4, IL-5, IL-8, and eotaxin production. Unlike the IL-2 inhibitors, cyclosporine and FK506, the BTPs do not directly inhibit the dephosphorylation of NFAT by calcineurin.

Synthesis of (+)-dynemicin A and analogs of wide structural variability: establishment of the absolute configuration of natural dynemicin A.

BACKGROUND: Dynemicin A is an exceedingly potent antitumor antibiotic derived from microbial fermentation that cleaves double-stranded B-form DNA in vitro in the presence of activating factors such as NADPH or glutathione. Because of the structural complexity, high reactivity, and scarcity of natural dynemicin A, it has not been feasible to modify the structure to any significant extent. Previous studies have not determined the absolute configuration of the natural product. RESULTS: A multistep route for the preparation of enantiomerically pure, synthetic dynemicin A was developed. The absolute configuration of natural dynemicin was determined by comparing the synthetic drug with dynemicin A derived from fermentation. The route that was developed is highly convergent, as the result of a late-stage coupling reaction that combines two complex synthetic fragments, and has been shown to provide access to non-natural dynemicins of wide structural variability by modifications of these fragments. In this way, several nonnatural dynemicins, unavailable by any other means, were synthesized and shown to have DNA-cleaving activity in the presence of glutathione or NADPH. CONCLUSIONS: Enantiomerically pure dynemicin A is now available by laboratory synthesis. The natural, (+)-enantiomer of dynemicin A is shown to possess the 2S, 3S, 4S, 7R, 8R configuration. A wide variety of heretofore unavailable, active analogs of dynemicin A have been prepared and are found to produce subtle variations in sequence specificity of DNA cleavage compared to the natural product and, of potentially greater significance, display variations in the efficiency of DNA cleavage as a function of the activating agent.