Hyperglucagonemia is implicated in the pathophysiology of hyperglycemia. Antagonism of the glucagon receptor (GCGR) thus represents a potential approach to diabetes treatment. Herein we report the ...characterization of GRA1, a novel small-molecule GCGR antagonist that blocks glucagon binding to the human GCGR (hGCGR) and antagonizes glucagon-induced intracellular accumulation of cAMP with nanomolar potency. GRA1 inhibited glycogenolysis dose-dependently in primary human hepatocytes and in perfused liver from hGCGR mice, a transgenic line of mouse that expresses the hGCGR instead of the murine GCGR. When administered orally to hGCGR mice and rhesus monkeys, GRA1 blocked hyperglycemic responses to exogenous glucagon. In several murine models of diabetes, acute and chronic dosing with GRA1 significantly reduced blood glucose concentrations and moderately increased plasma glucagon and glucagon-like peptide-1. Combination of GRA1 with a dipeptidyl peptidase-4 inhibitor had an additive antihyperglycemic effect in diabetic mice. Hepatic gene-expression profiling in monkeys treated with GRA1 revealed down-regulation of numerous genes involved in amino acid catabolism, an effect that was paralleled by increased amino acid levels in the circulation. In summary, GRA1 is a potent glucagon receptor antagonist with strong antihyperglycemic efficacy in preclinical models and prominent effects on hepatic gene-expression related to amino acid metabolism.
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G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote glucose-stimulated insulin secretion. Herein, we report ...our efforts to develop highly selective and potent GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion. Employing strategies to increase polarity and the ratio of sp3/sp2 character of the chemotype, we identified BMS-986118 (compound 4), which showed potent and selective GPR40 agonist activity in vitro. In vivo, compound 4 demonstrated insulinotropic efficacy and GLP-1 secretory effects resulting in improved glucose control in acute animal models.
The discovery and SAR study of a novel 1,3,5-pyrazole series of human glucagon receptor antagonists represented by 26 are presented. Compound 26 was selective and orally active in several in vivo ...preclinical models of type II diabetes.
A novel class of 1,3,5-pyrazoles has been discovered as potent human glucagon receptor antagonists. Notably, compound 26 is orally bioavailable in several preclinical species and shows selectivity towards cardiac ion channels, other family B receptors such hGIP and hGLP1, and a large panel of enzymes and additional receptors. When dosed orally, compound 26 is efficacious in suppressing glucagon induced plasma glucose excursion in rhesus monkey and transgenic murine pharmacodynamic models at 1 and 10mpk, respectively.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A novel class of antagonists of the human glucagon receptor (hGCGR) has been discovered. An SAR exploration of the lead class resulted in
13, which exhibited good potency as an hGCGR functional ...antagonist (IC
50
=
34
nM) and moderate bioavailability (36% in mice).
A novel class of antagonists of the human glucagon receptor (hGCGR) has been discovered. Systematic modification of the lead compound identified substituents that were essential for activity and those that were amenable to further optimization. This SAR exploration resulted in the synthesis of
13, which exhibited good potency as an hGCGR functional antagonist (IC
50
=
34
nM) and moderate bioavailability (36% in mice).
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The interviews in this collection cover Walter Mosley's career and reveal an overarching theme: a belief in the transformative power of reading and writing. Since the 1990 publication of his first ...novel, Devil in a Blue Dress, Mosley (b. 1952) has published over thirty books in a tremendous range of genres and modes: crime and detective fiction, science fiction, literary novels of ideas, character studies, political and social nonfiction, erotica, and memoir. Best known for his Easy Rawlins detective series and Socrates Fortlow series of crime novels, Mosley has created a body of work that as a whole chronicles and examines twentieth-century African American experience.Conversations with Walter Mosley covers the breadth of Mosley's career and reveals a craftsman and wryly witty conversationalist. Conscious of his forebears as well as literary techniques, he discusses favorites and influences including Camus, Shakespeare, and Dickens as well as writers in popular genres, especially speculative fiction and the hard-boiled noir detective tradition. He also discusses how his work modifies the crime tradition to engage it with black experience.
Introduction This survey reports the incidence of traumatic dental injuries in an adult population attending an adult dental trauma clinic in a London teaching hospital.Materials and methods ...Retrospective data were collected from patients attending an adult dental trauma clinic between 2012 and 2018.Results In total, 1,769 patients attended, with more men seen (1,030; 58.2%) compared to women (739; 41.8%) and this was statistically significant (p <0.05). The most common aetiological factor was an accidental fall (728; 41.15%), followed by assaults (413; 23.35%), bicycle accidents (253; 14.3%), sports injuries (132; 7.46%) and road traffic accidents (84; 4.75%). Lateral luxation (833) was the most common traumatic injury and this was followed by avulsions (362; 17%). Enamel-dentine fractures were the most common type of fracture injury (1,273; 64%).Discussion This retrospective survey attempts to report on the incidence of traumatic dental injuries in a London-based cohort of patients attending a specialised dental trauma clinic. In line with other reports, there were more men than women affected, which is probably attributed to behavioural activities.Conclusion(s) Accidental falls are the most common cause of a traumatic dental injury, lateral luxation was the most common type of displacement injury and enamel-dentine fractures were the most common type of fracture injury.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A series of conformationally constrained tri-substituted ureas (arrow indicates the position for conformation constraint in the Figure) were synthesized and their potential as the human glucagon ...receptor antagonists was evaluated. This effort resulted in the identification of compound
4a, which had a binding IC
50 of 4.0
nM and was shown to reduce blood glucose levels at 3
mg/kg in glucagon-challenged mice which contain a humanized glucagon receptor. Compound
4a was also efficacious in correcting hyperglycemia induced by a high fat diet in transgenic mice at doses as low as 3
mg/kg.
A series of conformationally constrained tri-substituted ureas were synthesized, and their potential as glucagon receptor antagonists was evaluated. This effort resulted in the identification of compound
4a, which had a binding IC
50 of 4.0
nM and was shown to reduce blood glucose levels at 3
mg/kg in glucagon-challenged mice containing a humanized glucagon receptor. Compound
4a was efficacious in correcting hyperglycemia induced by a high fat diet in transgenic mice at an oral dose as low as 3
mg/kg.
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Essays by Owen E. Brady, Kelly C. Connelly, Juan F. Elices, Keith Hughes, Derek C. Maus, Jerrilyn McGregory, Laura Quinn, Francesca Canadé Sautman, Daniel Stein, Lisa B. Thompson, Terrence Tucker, ...and Albert U. Turner, Jr.
In Finding a Way Home, thirteen essays by scholars from four countries trace Walter Mosley's distinctive approach to representing African American responses to the feeling of homelessness in an inhospitable America. Mosley (b. 1952) writes frequently of characters trying to construct an idea of home and wrest a sense of dignity, belonging, and hope from cultural and communal resources. These essays examine Mosley's queries about the meaning of "home" in various social and historical contexts. Essayists consider the concept--whether it be material, social, cultural, or virtual--in all three of Mosley's detective/crime fiction series (Easy Rawlins,Socrates Fortlow, andFearless Jones), his three books of speculative fiction, two of his "literary" novels (RL's Dream,The Man in My Basement), and in his recent social and political nonfiction.
Essays here explore Mosley's modes of expression, his testing of the limitations of genre, his political engagement in prose, his utopian/dystopian analyses, and his uses of parody and vernacular culture.Finding a Way Homeprovides rich discussions, explaining the development of Mosley's work.
The discovery and SAR study of a novel spiro-urea series of human glucagon receptor antagonists such as
15 are presented.
A novel class of spiro-ureas has been discovered as potent human glucagon ...receptor antagonists in both binding and functional assays. Preliminary studies have revealed that compound
15 is an orally active human glucagon receptor antagonist in a transgenic murine pharmacodynamic model at 10 and 30
mpk. Compound
15 is orally bioavailable in several preclinical species and shows selectivity toward cardiac ion channels and other family B receptors, such as hGIP1 and hGLP.
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Glucagon receptor antagonists have been actively pursued as potential therapeutics for the treatment of type 2 diabetes. Peptidyl and non-peptidyl glucagon receptor antagonists have been shown to ...block glucagon-induced blood glucose elevation in both animals and humans. How the antagonists and the glucagon receptor interact in vivo has not been reported and is the subject of the current study. Using
125I-labeled glucagon as a radiotracer, we developed an in vivo glucagon receptor occupancy assay in mice expressing a human glucagon receptor in place of the endogenous mouse glucagon receptor (hGCGR mice). Using this assay, we first showed that the glucagon receptor is expressed predominantly in liver, to a much lesser extent in kidney, and is below detection in several other tissues/organs in the mice. We subsequently showed that, at 2 mg/kg body weight (mg/pk) dosed intraperitoneally (i.p.), peptidyl glucagon receptor antagonist des-His-glucagon binds to ∼78% of the hepatic glucagon receptor and blocks an exogenous glucagon-induced blood glucose elevation in the mice. Finally, we also showed that, at 10 and 30 mg/kg dosed orally (p.o.), compound A, a non-peptidyl small molecule glucagon receptor antagonist, occupied 65–70% of the hepatic glucagon receptor, and significantly diminished exogenous glucagon-induced blood glucose elevation in the mice. At 3 mg/kg, however, compound A occupied only ∼39% of the hepatic glucagon receptor and did not affect exogenous glucagon-induced blood glucose elevation in the mice. Taken together, the results confirmed previous reports that glucagon receptors are present predominantly in the liver, and provide the first direct evidence that peptidyl and non-peptidyl glucagon receptor antagonists bind to the hepatic glucagon receptor in vivo, and that at least 60% receptor occupancy correlates with the glucose lowering efficacy by the antagonists in vivo.
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