Human glucagon receptor antagonists with thiazole cores. A novel series with superior pharmacokinetic properties.
ABSTRACT The aim of the work presented here was to design and synthesize potent human glucagon receptor antagonists with improved pharmacokinetic (PK) properties for development of pharmaceuticals for the treatment of type 2 diabetes. We describe the preparation of compounds with cyclic cores (5-aminothiazoles), their binding affinities for the human glucagon and GIP receptors, as well as affinities for rat, mouse, pig, dog, and monkey glucagon receptors. Generally, the compounds had slightly less glucagon receptor affinity compared to compounds of the previous series, but this was compensated for by much improved PK profiles in both rats and dogs with high oral bioavailabilities and sustained high plasma exposures. The compounds generally showed species selectivity for glucagon receptor binding with poor affinities for the rat, mouse, rabbit, and pig receptors. However, dog and monkey glucagon receptor affinities seem to reflect the human situation. One compound of this series, 18, was tested intravenously in an anesthetized glucagon-challenged monkey model of hyperglucagonaemia and hyperglycaemia and was shown dose-dependently to decrease glycaemia. Further, high plasma exposures and a long plasma half-life (5.2 h) were obtained.
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ABSTRACT: Epilepsy has been reported in patients with pervasive developmental disorder (PDD), with an incidence ranging from 5% to 40%; however most of the studies included patients with brain magnetic resonance imaging (MRI) abnormalities (e.g., tuberous sclerosis) and patients with epilepsy whose seizure onset was in the first year of life. We retrospectively examined 67 patients (45 males, 22 females) with PDD and epilepsy, who did not have brain MRI abnormalities. Patients who had seizures in the first year of life were excluded. We divided the patients into two groups: group A included 34 patients with an IQ<50, and group B included 33 patients with an IQ≥50. The median age of epilepsy onset was higher in group A than group B (8.8 vs. 5.2 years, P<0.01). Only one patient (3%) in group A and nine patients (27%) in group B were classified with generalized epilepsy (P<0.05). At the last observation, 16 patients (47%) in group A and 25 patients (76%) in group B were seizure-free for ≥1year (not statistically significant). The relationship between PDD and epilepsy may be different between patients with lower (group A) and higher (group B) IQs in patients who do not have brain MRI abnormalities.Brain & development 06/2011; 33(6):504-7. · 1.74 Impact Factor
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ABSTRACT: The increasing prevalence, variable pathogenesis, progressive natural history, and complications of type 2 diabetes emphasise the urgent need for new treatment strategies. Longacting (eg, once weekly) agonists of the glucagon-like-peptide-1 receptor are advanced in development, and they improve prandial insulin secretion, reduce excess glucagon production, and promote satiety. Trials of inhibitors of dipeptidyl peptidase 4, which enhance the effect of endogenous incretin hormones, are also nearing completion. Novel approaches to glycaemic regulation include use of inhibitors of the sodium-glucose cotransporter 2, which increase renal glucose elimination, and inhibitors of 11β-hydroxysteroid dehydrogenase 1, which reduce the glucocorticoid effects in liver and fat. Insulin-releasing glucokinase activators and pancreatic-G-protein-coupled fatty-acid-receptor agonists, glucagon-receptor antagonists, and metabolic inhibitors of hepatic glucose output are being assessed. Early proof of principle has been shown for compounds that enhance and partly mimic insulin action and replicate some effects of bariatric surgery.The Lancet 06/2011; 378(9786):182-97. · 39.06 Impact Factor
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ABSTRACT: Acute in vitro and in vivo biological activities of four novel structural analogues of glucagon were tested. desHis(1)Pro(4)-glucagon, desHis(1)Pro(4)Glu(9)-glucagon, desHis(1)Pro(4)Glu(9)Lys(12)FA-glucagon and desHis(1)Pro(4)Glu(9)Lys(30)FA-glucagon were stable to DPP-4 degradation and dose-dependently inhibited glucagon-mediated cAMP production (p<0.05 to p<0.001). None stimulated insulin secretion in vitro above basal levels, but all inhibited glucagon-induced insulin secretion (p<0.01 to p<0.001). In normal mice all analogues antagonised acute glucagon-mediated elevations of blood glucose (p<0.05 to p<0.001) and blocked corresponding insulinotropic responses. In high-fat fed mice, glucagon-induced increases in plasma insulin (p<0.05 to p<0.001) and glucagon-induced hyperglycaemia were blocked (p<0.05 to p<0.01) by three analogues. In obese diabetic (ob/ob) mice only desHis(1)Pro(4)Glu(9)-glucagon effectively (p<0.05 to p<0.01) inhibited both glucagon-mediated glycaemic and insulinotropic responses. desHis(1)Pro(4)-glucagon and desHis(1)Pro(4)Glu(9)-glucagon were biologically ineffective when administered 8 h prior to glucagon, whereas desHis(1)Pro(4)Glu(9)Lys(12)FA-glucagon retained efficacy (p<0.01) for up to 24 h. Such peptide-derived glucagon receptor antagonists have potential for type 2 diabetes therapy.Molecular and Cellular Endocrinology 07/2013; · 4.04 Impact Factor