HIS-388, a Novel Orally Active and Long-Acting 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor, Ameliorates Insulin Sensitivity and Glucose Intolerance in Diet-Induced Obesity and Nongenetic Type 2 Diabetic Murine Models

Abstract

11b-Hydroxysteroid dehydrogenase type 1 (11b-HSD1) is considered a potential therapeutic target in the treatment of type 2 diabetes mellitus. In this study, we investigated the pharmacological properties of 2s,3S,5s,7s)-5-hydroxyadamantan-2-yl]-3-(pyridin-2-yl) isoxazole-4-carboxamide), a newly synthesized 11b-HSD1 inhibitor, using several mouse models. In cortisone pellet-implanted mice in which hypercortisolism and hyperinsulinemia occur, single administration of HIS-388 exhibited potent and prolonged suppression of plasma cortisol and lowered plasma insulin levels. These effects were more potent than those achieved using the same dose of other 11b-HSD1 inhibitors (carbenoxolone and compound 544 [3-[(1s,3s)-adamantan-1-yl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine]), indicating that HIS-388 potently and continuously suppresses 11b-HSD1 enzyme activity in vivo. In diet-induced obese mice, HIS-388 significantly decreased fasting blood glucose, plasma insulin concentration, and homeostasis model assessment-insulin resistance score, and ameliorated insulin sensitivity. In addition, HIS-388 significantly reduced body weight and suppressed the elevation of blood glucose during the pyruvate tolerance test. In nongenetic type 2 diabetic mice with disease induced by a high-fat diet and low-dose streptozotocin, HIS-388 also significantly decreased postprandial blood glucose and plasma insulin levels and improved glucose intolerance. The effects of HIS-388 on glucose metabolism were indistinguishable from those of an insulin sensitizer, pioglitazone. Our results suggest that HIS-388 is a potent agent against type 2 diabetes. Moreover, amelioration of diabetic symptoms by HIS-388 was at least in part attributable to an antiobesity effect or improvement of hepatic insulin resistance. Therefore, potent and long-lasting inhibition of 11b-HSD1 enzyme activity may be an effective approach for the treatment of type 2 diabetes and obesityassociated disease.

Glucocorticoids and non-alcoholic fatty liver disease

“…Subcutaneous injection of Carbenoxolone, a non-selective 11β-HSD inhibitor, administered to rodents improved parameters of the metabolic syndrome including hepatic steatosis (114). Several studies using rodent models have examined the effects of selective 11β-HSD1 inhibitors upon liver phenotype (115,116). The majority of compounds used are still in early development with rodent models predominantly being used to assess safety and efficacy.…”

Impact of postprandial glucose control on diabetes-related complications: How is the evidence evolving?

“…Decrease in fasting glucose, reduced insulin resistance and improved glucose tolerance [81,97] Glucokinase activators Small-molecule glucokinase activators (e.g. piragliatin)…”

Discovery of Novel Insulin Sensitizers: Promising Approaches and Targets

“…Animal studies have shown that adipose-specific 11 β -HSD1 knockout mice are refractory to diet-induced obesity and show improved glucose tolerance and insulin sensitivity, whereas transgenic mice overexpressing 11 β -HSD1 in fat cells have been found to develop glucose intolerance, IR, and dyslipidemia [90, 91]. As inhibition of 11 β -HSD1 can decrease the levels of active GCs owing to its specific role in GC interconversion, 11 β -HSD1 has been considered an attractive therapeutic target for the treatment of IR, T2DM, and metabolic syndrome [87, 92]. …”

“…Several structurally diverse and selective 11 β -HSD1 inhibitors, such as HIS-388, LG13, and PF-915275, have thus been designed [92, 93]. The antidiabetic activity of these inhibitors has been confirmed to be comparable to that of the classical insulin sensitizer pioglitazone in different insulin-resistant and/or diabetic rodent models [92, 94, 95], where the inhibitors significantly suppressed the levels of plasma and local tissue cortisol, plasma insulin, and fasting or postprandial blood glucose, and improved glucose intolerance and IR.…”