Chapter 19. Glucagon and Glucagon-Like Peptide-1

Livingston, James N.; Schoen, William R.

doi:10.1016/s0065-7743(08)60581-3

Cited by 18 publications

(7 citation statements)

References 55 publications

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“…Glucagon receptor antagonists have been the subject of a recent comprehensive review article [39]. Reports describing the discovery and optimization of potent, orally absorbed glucagon receptor antagonists, typified by L-168,049 10 (K b =25 nM, non-competitive with glucagon), have appeared.…”

Section: Glucagon Receptor Antagonistsmentioning

confidence: 99%

Current Therapies and Emerging Targets for the Treatment of Diabetes

Wagman¹,

Nuss²

2001

CPD

155

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Concurrent with the spread of the western lifestyle, the prevalence of all types of diabetes is on the rise in the world's population. The number of diabetics is increasing by 4-5% per year with an estimated 40-45% of individual's over the age of 65 years having either type II diabetes or impaired glucose tolerance. Since the signs of diabetes are not immediately obvious, diagnosis can be preceded by an extended period of impaired glucose tolerance resulting in the prevalence of beta-cell dysfunction and macrovascular complications. In addition to increased medical vigilance, diabetes is being combatted through aggressive treatment directed at lowering circulating blood glucose and inhibiting postprandial hyperglycemic spikes. Current strategies to treat diabetes include reducing insulin resistance using glitazones, supplementing insulin supplies with exogenous insulin, increasing endogenous insulin production with sulfonylureas and meglitinides, reducing hepatic glucose production through biguanides, and limiting postprandial glucose absorption with alpha-glucosidase inhibitors. In all of these areas, new generations of small molecules are being investigated which exhibit improved efficacy and safety profiles. Promising biological targets are also emerging such as (1) insulin sensitizers including protein tyrosine phosphatase-1B (PTP-1B) and glycogen synthase kinase 3 (GSK3), (2) inhibitors of gluconeogenesis like pyruvate dehydrogenase kinase (PDH) inhibitors, (3) lipolysis inhibitors, (4) fat oxidation including carnitine palmitoyltransferase (CPT) I and II inhibitors, and (5) energy expenditure by means of beta 3-adrenoceptor agonists. Also important are alternative routes of glucose disposal such as Na+-glucose cotransporter (SGLT) inhibitors, combination therapies, and the treatment of diabetic complications (eg. retinopathy, nephropathy, and neuropathy). With may new opportunities for drug discovery, the prospects are excellent for development of innovative therapies to effectively manage diabetes and prevent its long term complications. This review highlights recent (1997-2000) advances in diabetes therapy and research with an emphasis on small molecule drug design (275 references).

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Section: Glucagon Receptor Antagonistsmentioning

confidence: 99%

Current Therapies and Emerging Targets for the Treatment of Diabetes

Wagman¹,

Nuss²

2001

CPD

155

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“…12 A few classes of non-peptide glucagon receptor antagonists have recently been published, primarily by scientists from Merck, Bayer, and Novo Nordisk. [14][15][16][17] Previously we have published 18 the discovery of a new class of human glucagon receptor (hGluR) antagonists, alkylidene hydrazides (1), and the subsequent optimization leading to 2 19 (see Figure 1). In the present publication, further optimization of these two compounds are reported leading to series of high-affinity hGluR antagonists.…”

Section: Introductionmentioning

confidence: 99%

Optimization of Alkylidene Hydrazide Based Human Glucagon Receptor Antagonists. Discovery of the Highly Potent and Orally Available 3-Cyano-4-hydroxybenzoic Acid [1-(2,3,5,6-Tetramethylbenzyl)-1H-indol-4-ylmethylene]hydrazide

et al. 2002

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Highly potent human glucagon receptor (hGluR) antagonists have been prepared employing both medicinal chemistry and targeted libraries based on modification of the core (proximal) dimethoxyphenyl group, the benzyl ether linkage, as well as the (distal) benzylic aryl group of the lead 2, 3-cyano-4-hydroxybenzoic acid (3,5-dimethoxy-4-isopropylbenzyloxybenzylidene)hydrazide. Electron-rich proximal aryl moieties such as mono- and dimethoxy benzenes, naphthalenes, and indoles were found to be active. The SAR was found to be quite insensitive regarding the linkage to the distal aryl group, since long and short as well as polar and apolar linkers gave highly potent compounds. The presence of a distal aryl group was not crucial for obtaining high binding affinity to the hGluR. In many cases, however, the affinity could be further optimized with substituted distal aryl groups. Representative compounds have been tested for in vitro metabolism, and structure-metabolism relationships are described. These efforts lead to the discovery of 74, NNC 25-2504, 3-cyano-4-hydroxybenzoic acid [1-(2,3,5,6-tetramethylbenzyl)-1H-indol-4-ylmethylene]hydrazide, with low in vitro metabolic turnover. 74 was a highly potent noncompetitive antagonist of the human glucagon receptor (IC(50) = 2.3 nM, K(B) = 760 pM) and of the isolated rat receptor (IC(50) = 430 pM, K(B) = 380 pM). Glucagon-stimulated glucose production from isolated primary rat hepatocytes was inhibited competitively by 74 (K(i) = 14 nM). This compound was orally available in dogs (F(po) = 15%) and was active in a glucagon-challenged rat model of hyperglucagonemia and hyperglycemia.

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“…The effects of glucagon were markedly blunted in the high-dose group a half-life of 11-17 h in male rats. In efficacy studies, an oral dose of 200 mg of 23 almost completely blocked glucagon-induced increase in hepatic glucose output and reduced blood glucose elevation in normal males (31).…”

Section: -Pyridyl-35-diaryl Pyrrolesmentioning

confidence: 93%

“…Binding affinities of selected 4-arylpyridines and biphenyls for various glucagon receptors(27,28,31,32).…”

mentioning

confidence: 99%