Progress in 11β-HSD1 inhibitors for the treatment of metabolic diseases: A comprehensive guide to their chemical structure diversity in drug development

Zhong, Chuanxin; Wang, Shengzheng; Dang, Lei; Xie, Dizhi; Jin, Liu; Ren, Fuzeng; Lü, Aiping; Zhang, Ge

doi:10.1016/j.ejmech.2020.112134

Cited by 23 publications

(20 citation statements)

References 80 publications

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“…10,19 AZD4017 is only one of at least 25 drugs that have been evaluated recently as 11β-HSD1 inhibitors in clinical trials. 41 Like other synthetic 11β-HSD1 inhibitors, AZD4017 exhibits high potency [IC50 (Half-maximal inhibitory concentration)= 7 nM] and excellent in vivo pharmacokinetic and biodistribution profiles. 42 However, none of these drugs have been approved for use, mostly due to their limited therapeutic potency and potential safety concerns primarily related to activation of the HPA axis.…”

Section: Discussionmentioning

confidence: 99%

“…AZD4017 is only one of at least 25 drugs that have been evaluated recently as 11β‐HSD1 inhibitors in clinical trials 41 . Like other synthetic 11β‐HSD1 inhibitors, AZD4017 exhibits high potency [IC50 (Half‐maximal inhibitory concentration)= 7 nM] and excellent in vivo pharmacokinetic and biodistribution profiles 42 .…”

Section: Discussionmentioning

confidence: 99%

“…A review by Chuanxin et al provides several possible reasons as to why AZD4017 and other synthetic 11β-HSD1 inhibitors may have failed clinical evaluations: the animal models available are not suitable to assess the inhibitory effects of these drugs because there are major differences in the 11β-HSD1 activity in humans and rodents and/or inhibition may lead to HPA axis activation. 41 …”

Section: Discussionmentioning

confidence: 99%

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Inhibition of 11β‐Hydroxysteroid dehydrogenase‐1 with AZD4017 in patients with nonalcoholic steatohepatitis or nonalcoholic fatty liver disease: A randomized, double‐blind, placebo‐controlled, phase II study

Yadav

Dunagan

Khot

et al. 2022

Diabetes Obesity Metabolism

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Aim: To evaluate whether short-term treatment with a selective 11β-Hydroxysteroid dehydrogenase-1 (11β-HSD1) inhibitor, AZD4017, would block hepatic cortisol production and thereby decrease hepatic fat in patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), with or without type 2 diabetes (T2D).Materials and Methods: This was a randomized, double-blind, placebo-controlled, phase 2 study conducted at two sites. Key inclusion criteria were the presence of NAFLD or NASH on magnetic resonance imaging (MRI) or recent biopsy positive for NASH. Enrolled patients were randomly assigned (1:1) to AZD4017 or placebo for 12 weeks. Primary outcomes were between-group differences in mean change from baseline to week 12 in liver fat fraction (LFF) and conversion of 13 C cortisone to 13 C cortisol in the liver.Results: A total of 93 patients were randomized; 85 patients completed treatment.The mean (standard deviation [SD]) change in LFF was À0.667 (5.246) and 0.139 (4.323) in the AZD4017 and placebo groups (P = 0.441). For patients with NASH and T2D, the mean (SD) change in LFF was significantly improved in the AZD4017 versus the placebo group (À1.087 [5.374] vs. 1.675 [3.318]; P = 0.033). Conversion of 13 C cortisone to 13 C cortisol was blocked in all patients in the AZD4017 group. There were no significant between-group differences (AZD4017 vs. placebo) in changes in fibrosis, weight, levels of liver enzymes or lipids, or insulin sensitivity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Inhibition of 11β‐Hydroxysteroid dehydrogenase‐1 with AZD4017 in patients with nonalcoholic steatohepatitis or nonalcoholic fatty liver disease: A randomized, double‐blind, placebo‐controlled, phase II study

Yadav

Dunagan

Khot

et al. 2022

Diabetes Obesity Metabolism

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“…(CBG) directly through hyperinsulinemia; lastly and with a potential therapeutic impact, insulin resistance and diabetes/prediabetes may be able to induce an increase in 11 β‐Hydroxysteroid dehydrogenase type 1 (11β‐HSD1) enzyme activity 38 . Selective 11β‐HSD1 inhibitors, decreasing the conversion of cortisone to biologically active cortisol, might be useful to improve insulin sensitivity and glucose tolerance in key metabolic tissues, including skeletal muscle, liver and adipose tissue 39 …”

Section: Discussionmentioning

confidence: 99%

Hypercortisolism and altered glucose homeostasis in obese patients in the pre‐bariatric surgery assessment

Muraca

Ciardullo

Perra

et al. 2020

Diabetes Metabolism Res

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Aims Hypothalamus‐pituitary‐adrenal (HPA) axis hyperactivity was suggested to be associated with the metabolic syndrome (MS), obesity and diabetes. The aim of this study was to test whether hypercortisolism was associated with altered glucose homeostasis and insulin resistance, hypertension and dyslipidemia in a homogeneous population of obese patients. Materials/Methods In retrospective analysis of a set of data about obese patients attending the outpatient service of a single obesity centre between January 2013 and January 2020, 884 patients with BMI >30 kg/m2 were segregated in two subgroups: patients with urinary free cortisol (UFC) higher than normal (UFC+; n = 129) or within the normal range (UFC−; n = 755). Results The overall prevalence of UFC+ was 14.6% and double test positivity (morning cortisol >1.8 mcg/dL following overnight dexamethasone suppression test, ODST) was detected in 1.0% of patients. Prediabetes (OR 1.74; 95%CI 1.13‐2.69; p = 0.012) and diabetes (OR 2.03; 95%CI 1.21‐3.42; p = 0.008) were associated with higher risk of UFC+ when analysis was adjusted for confounding variables. Conversely, hypertension and dyslipidemia were not related to UFC+. Within the individuals with normal FPG and HbA1c, those with higher estimated insulin resistance (HOMA2‐IR) maintained a higher risk of UFC+ (OR 2.84, 95%CI 1.06‐7.63; p = 0.039) and this relationship was weakened only when the body fat percentage was included into the model. Conclusions In obese patients, hypercortisolism was more frequent across the entire spectrum of altered glucose homeostasis including the very early stages; this relation could not be detected for the other criteria of the MS, as waist, hypertension and atherogenic dyslipidemia.

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“…Numerous compounds targeting 11 β -HSD1 are under investigation, including natural products such as glycyrrhetinic acid and resveratrol, in the search for a therapeutic approach to NAFLD. However, unselective inhibition of 11 β -HSD1 accelerates the activation of HSCs in the liver [ 108 ], suggesting that suitable target tissues should be established to bring into full play its inhibitory potency and low toxicity [ 114 ].…”

Section: Transcriptional Regulation Of Lipid Metabolism By Nrs In Nafldmentioning

confidence: 99%

The Role and Mechanism of Oxidative Stress and Nuclear Receptors in the Development of NAFLD

Hong

Chen

et al. 2021

Oxidative Medicine and Cellular Longevity

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The overproduction of reactive oxygen species (ROS) and consequent oxidative stress contribute to the pathogenesis of acute and chronic liver diseases. It is now acknowledged that nonalcoholic fatty liver disease (NAFLD) is characterized as a redox-centered disease due to the role of ROS in hepatic metabolism. However, the underlying mechanisms accounting for these alternations are not completely understood. Several nuclear receptors (NRs) are dysregulated in NAFLD, and have a direct influence on the expression of a set of genes relating to the progress of hepatic lipid homeostasis and ROS generation. Meanwhile, the NRs act as redox sensors in response to metabolic stress. Therefore, targeting NRs may represent a promising strategy for improving oxidation damage and treating NAFLD. This review summarizes the link between impaired lipid metabolism and oxidative stress and highlights some NRs involved in regulating oxidant/antioxidant turnover in the context of NAFLD, shedding light on potential therapies based on NR-mediated modulation of ROS generation and lipid accumulation.

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Progress in 11β-HSD1 inhibitors for the treatment of metabolic diseases: A comprehensive guide to their chemical structure diversity in drug development

Cited by 23 publications

References 80 publications

Inhibition of 11β‐Hydroxysteroid dehydrogenase‐1 with AZD4017 in patients with nonalcoholic steatohepatitis or nonalcoholic fatty liver disease: A randomized, double‐blind, placebo‐controlled, phase II study

Inhibition of 11β‐Hydroxysteroid dehydrogenase‐1 with AZD4017 in patients with nonalcoholic steatohepatitis or nonalcoholic fatty liver disease: A randomized, double‐blind, placebo‐controlled, phase II study

Hypercortisolism and altered glucose homeostasis in obese patients in the pre‐bariatric surgery assessment

The Role and Mechanism of Oxidative Stress and Nuclear Receptors in the Development of NAFLD

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