As a counterregulatory hormone for insulin, glucagon plays a critical role in maintaining glucose homeostasis in vivo in both animals and humans. To increase blood glucose, glucagon promotes hepatic glucose output by increasing glycogenolysis and gluconeogenesis and by decreasing glycogenesis and glycolysis in a concerted fashion via multiple mechanisms. Compared with healthy subjects, diabetic patients and animals have abnormal secretion of not only insulin but also glucagon. Hyperglucagonemia and altered insulin-to-glucagon ratios play important roles in initiating and maintaining pathological hyperglycemic states. Not surprisingly, glucagon and glucagon receptor have been pursued extensively in recent years as potential targets for the therapeutic treatment of diabetes.

Glucagon and regulation of glucose metabolism

Peptide hormones within the secretin-glucagon family are expressed in endocrine cells of the pancreas and gastrointestinal epithelium and in specialized neurons in the brain, and subserve multiple biological functions, including regulation of growth, nutrient intake, and transit within the gut, and digestion, energy absorption, and energy assimilation. Glucagon, glucagon-like peptide-1, glucagon-like peptide-2, glucose-dependent insulinotropic peptide, growth hormone-releasing hormone and secretin are structurally related peptides that exert their actions through unique members of a structurally related G protein-coupled receptor class 2 family. This review discusses advances in our understanding of how these peptides exert their biological activities, with a focus on the biological actions and structural features of the cognate receptors. The receptors have been named after their parent and only physiologically relevant ligand, in line with the recommendations of the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR).

https://pharmrev.aspetjournals.org/content/pharmrev/55/1/167.full.pdf

International Union of Pharmacology. XXXV. The Glucagon Receptor Family

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

Modulators of atp-binding cassette transporters

The hyperglycemic activity of pancreatic extracts was encountered some 80 yr ago during efforts to optimize methods for the purification of insulin. The hyperglycemic substance was named "glucagon," and it was subsequently determined that glucagon is a 29-amino acid peptide synthesized and released from pancreatic alpha-cells. This article begins with a brief overview of the discovery of glucagon and the contributions that somatostatin and a sensitive and selective assay for pancreatic (vs. gut) glucagon made to understanding the physiological and pathophysiological roles of glucagon. Studies utilizing these tools to establish the function of glucagon in normal nutrient homeostasis and to document a relative glucagon excess in type 2 diabetes mellitus (T2DM) and precursors thereof are then discussed. The evidence that glucagon excess contributes to the development and maintenance of fasting hyperglycemia and that failure to suppress glucagon secretion contributes to postprandial hyperglycemia is then reviewed. Although key human studies are emphasized, salient animal studies highlighting the importance of glucagon in normal and defective glucoregulation are also described. The past eight decades of research in this area have led to development of new therapeutic approaches to treating T2DM that have been shown to, or are expected to, improve glycemic control in patients with T2DM in part by improving alpha-cell function or by blocking glucagon action. Accordingly, this review ends with a discussion of the status and therapeutic potential of glucagon receptor antagonists, alpha-cell selective somatostatin agonists, glucagon-like peptide-1 agonists, and dipeptidyl peptidase-IV inhibitors. Our overall conclusions are that there is considerable evidence that relative hyperglucagonemia contributes to fasting and postprandial hyperglycemia in patients with T2DM, and there are several new and emerging pharmacotherapies that may improve glycemic control in part by ameliorating the hyperglycemic effects of this relative glucagon excess.

The role of alpha-cell dysregulation in fasting and postprandial hyperglycemia in type 2 diabetes and therapeutic implications.

The invention provides a novel class of compounds of formula 1, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of B-Raf

Compounds and compositions as protein kinase inhibitors

A coumpound of the formula (I) wherein each X is independently NR1R6, NR4R5, or R4, with the proviso that at least one X must be NR1R6; each R1 is independently an optionally substituted fused bicyclic unsaturated ring containing 9 or 10 atoms optionally containing 1-4 heteroatoms selected from the group consisting of N, S and O, and the variables R2-6 are as defined in claim 1, are claimed. These compounds are kinase inhibitors useful in the treatment of cancer and viral infections.

2- and 4-aminopyrimidines n-substtituded by a bicyclic ring for use as kinase inhibitors in the treatment of cancer

Substituted pyridines of formula (IA) are produced by reaction of suitably substituted pyridylaldehydes with Grignard or Witting reagents, and the resulting products are appropriately reduced. The pyridines of formula (IA) are suitable as active compounds in pharmaceutical products, particularly in pharmaceutical products for the inhibition of cholesterol ester transfer proteins. 3-Heteroalkyl-aryl-substituted pyridines of formula (IB) are produced from pyridines which are correspondingly protected at the hydroxy group and correspondingly substituted. The compounds of formula (IB) according to the invention are suitable as active compounds in pharmaceutical products, particularly pharmaceutical products for the treatment of hyperlipoproteinemia. Substituted pyridines and benzenes of formula (IC) are produced by procedures disclosed herein, and are useful as active ingredients in pharmaceutical products, particularly pharmaceutical products for inhibition of the glucagon receptor, leading to treatment of glucagon-mediated conditions such as diabetes.

Substituted pyridines and biphenyls as anti-hypercholesterinemic, anti-hyperlipoproteinemic and anti-hyperglycemic agents

The present invention relates to compounds of formula (I), pharmaceutical compositions which contain them and methods for treating cancer using compounds of formula (I).

Substituted pyrazolyl urea derivatives useful in the treatment of cancer

The present invention provides methods of using aryl ureas to treat diseases and conditions associated with signal transduction pathways comprising at least one of raf, VEGFR, PDGFR, p38 and/or FLT-3. The present invention also provides compositions and methods for identifying conditions and diseases which can be modulated with compounds of the present invention. These methods facilitate the selection of subjects who can be efficiently treated with compounds of the present invention. Additionally, the invention provides methods for monitoring subjects who have been administered a compound of the present invention.

Diaryl ureas with kinase inhibiting activity

Pyrazole urea compounds, pharmaceutical compositions which contain them and methods for treating cancer using them.

Gaetan H. Ladouceur

Papers

2- and 4-aminopyrimidines n-substtituded by a bicyclic ring for use as kinase inhibitors in the treatment of cancer

Substituted pyridines and biphenyls as anti-hypercholesterinemic, anti-hyperlipoproteinemic and anti-hyperglycemic agents

Substituted pyrazolyl urea derivatives useful in the treatment of cancer

Diaryl ureas with kinase inhibiting activity

Urea compounds useful in the treatment of cancer