[reaction: see text] Treatment of a variety of alcohols, amines, and N-hydroxylamines with 2,2,2-trifluoroethyl formate gave the corresponding formylated adducts in high yields.
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.
Checkpoint
inhibitors have demonstrated unprecedented efficacy
and are evolving to become standard of care for certain types of cancers.
However, low overall response rates often hamper the broad utility
and potential of these breakthrough therapies. Combination therapy
strategies are currently under intensive investigation in the clinic,
including the combination of PD-1/PD-L1 agents with IDO1 inhibitors.
Here, we report the discovery of a class of IDO1 heme-binding inhibitors
featuring a unique amino-cyclobutarene motif, which was discovered
through SBDD from a known and weakly active inhibitor. Subsequent
optimization efforts focused on improving metabolic stability and
were greatly accelerated by utilizing a robust SNAr reaction
of a facile nitro-furazan intermediate to quickly explore different
polar side chains. As a culmination of these efforts, compound 16 was identified and demonstrated a favorable overall profile
with superior potency and selectivity. Extensive studies confirmed
the chemical stability and drug-like properties of compound 16, rendering it a potential drug candidate.
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.
[reaction: see text] Purines, xanthines, and other fused imidazoles can be prepared from amidines or guanidines, with retrosynthetic disconnection at the ring fusion. Ring closure proceeds using Cu(I), with no special ligands required. The method allows for easy modification of the heterocyclic nucleus and is tolerant of functionality pendant to the ring system.
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