Chapter 5. 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors in Development

Scott, James S.; Chooramun, Jasen

doi:10.1039/9781849735322-00109

Cited by 7 publications

(6 citation statements)

References 78 publications

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“…Adamantane derivatives constitutes the major class of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor, which are considered important therapy for controlling non-insulin-dependent diabetes, hyperglycemia, obesity, insulin resistance, hyperlipidemia, hypertension and other symptoms associated with excessive body cortisol [ 30 , 31 ]. MK-544 (XII) [ 32 ], PF-877423 (XIII) [ 33 ], AZD6925 (XIV) [ 34 ], are recently developed drug candidates for the treatment of non-insulin-dependent diabetes and obesity. Moreover, anti-inflammatory activity was reported in several adamantane-containing molecules [ 19 , 20 , 21 , 22 , 35 , 36 , 37 , 38 ].…”

Section: Introductionmentioning

confidence: 99%

Antimicrobial and Hypoglycemic Activities of Novel N-Mannich Bases Derived from 5-(1-Adamantyl)-4-substituted-1,2,4-triazoline-3-thiones

Al‐Abdullah

Al-Tuwaijri

Hassan

et al. 2014

IJMS

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The reaction of 5-(1-adamantyl)-4-ethyl or allyl-1,2,4-triazoline-3-thione with formaldehyde solution and various 1-substituted piperazines yielded the corresponding N-Mannich bases. The newly synthesized N-Mannich bases were tested for in vitro inhibitory activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Six compounds showed potent antibacterial activity against one or more of the tested microorganisms, while two compounds exhibited moderate activity against the tested Gram-positive bacteria. None of the newly synthesized compounds were proved to possess marked activity against Candida albicans. The oral hypoglycemic activity of six compounds was determined in streptozotocin (STZ)-induced diabetic rats. Four compounds produced significant strong dose-dependent reduction of serum glucose levels, compared to gliclazide at 10 mg/kg dose level (potency ratio > 75%).

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Section: Introductionmentioning

confidence: 99%

Antimicrobial and Hypoglycemic Activities of Novel N-Mannich Bases Derived from 5-(1-Adamantyl)-4-substituted-1,2,4-triazoline-3-thiones

Al‐Abdullah

Al-Tuwaijri

Hassan

et al. 2014

IJMS

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“…The adamantane-linked 1,2,4-triazole derivatives I , II and III were discovered as potent inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) [ 14 , 15 ]. In addition, the non-adamantyl 1,2,4-triazoles IV [ 16 ], V [ 17 ] and VI [ 18 ] are presently under clinical investigations as 11β-HSD1 inhibitors for the treatment of type 2 diabetes and obesity ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

“…The adamantane-linked 1,2,4-triazole derivatives I, II and III were discovered as potent inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) [14,15]. In addition, the non-adamantyl 1,2,4-triazoles IV [16], V [17] and VI [18] are presently under clinical investigations as 11β-HSD1 inhibitors for the treatment of type 2 diabetes and obesity (Figure 1). 11β-HSD1 is an endoplasmic reticulum-associated enzyme that acts as NADPHdependent reductase, it converts inactive cortisone to the active glucocorticoid cortisol.…”

Section: Introductionmentioning

confidence: 99%

Structural Insights and Docking Analysis of Adamantane-Linked 1,2,4-Triazole Derivatives as Potential 11β-HSD1 Inhibitors

et al. 2021

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The solid-state structural analysis and docking studies of three adamantane-linked 1,2,4-triazole derivatives are presented. Crystal structure analyses revealed that compound 2 crystallizes in the triclinic P-1 space group, while compounds 1 and 3 crystallize in the same monoclinic P21/c space group. Since the only difference between them is the para substitution on the aryl group, the electronic nature of these NO2 and halogen groups seems to have no influence over the formation of the solid. However, a probable correlation with the size of the groups is not discarded due to the similar intermolecular disposition between the NO2/Cl substituted molecules. Despite the similarities, CE-B3LYP energy model calculations show that pairwise interaction energies vary between them, and therefore the total packing energy is affected. HOMO-LUMO calculated energies show that the NO2 group influences the reactivity properties characterizing the molecule as soft and with the best disposition to accept electrons. Further, in silico studies predicted that the compounds might be able to inhibit the 11β-HSD1 enzyme, which is implicated in obesity and diabetes. Self- and cross-docking experiments revealed that a number of non-native 11β-HSD1 inhibitors were able to accurately dock within the 11β-HSD1 X-ray structure 4C7J. The molecular docking of the adamantane-linked 1,2,4-triazoles have similar predicted binding affinity scores compared to the 4C7J native ligand 4YQ. However, they were unable to form interactions with key active site residues. Based on these docking results, a series of potentially improved compounds were designed using computer aided drug design tools. The docking results of the new compounds showed similar predicted 11β-HSD1 binding affinity scores as well as interactions to a known potent 11β-HSD1 inhibitor.

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“…The adamantane-based drugs, vildagliptin [ 16 ], and saxagliptin [ 17 ] are currently used as oral hypoglycemic agents for the treatment of type 2 diabetes acting via inhibition of dipeptidyl peptidase IV (DPP-IV). Moreover, the adamantane derivatives MK-544 [ 18 ], PF-877423 [ 19 ], and AZD6925 [ 20 ] were recently developed as 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors as drug candidates for the treatment of non-insulin-dependent diabetes and obesity [ 21 ] ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

Adamantane-Isothiourea Hybrid Derivatives: Synthesis, Characterization, In Vitro Antimicrobial, and In Vivo Hypoglycemic Activities

et al. 2017

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A new series of adamantane-isothiourea hybrid derivatives, namely 4-arylmethyl (Z)-N′-(adamantan-1-yl)-morpholine-4-carbothioimidates 7a–e and 4-arylmethyl (Z)-N′-(adamantan-1-yl)-4-phenylpiperazine-1-carbothioimidates 8a–e were prepared via the reaction of N-(adamantan-1-yl)morpholine-4-carbothioamide 5 and N-(adamantan-1-yl)-4-phenylpiperazine-1-carbothioamide 6 with benzyl or substituted benzyl bromides, in acetone, in the presence of anhydrous potassium carbonate. The structures of the synthesized compounds were confirmed by 1H-NMR, 13C-NMR, electrospray ionization mass spectral (ESI-MS) data, and X-ray crystallographic data. The in vitro antimicrobial activity of the new compounds was determined against certain standard strains of pathogenic bacteria and the yeast-like pathogenic fungus Candida albicans. Compounds 7b, 7d and 7e displayed potent broad-spectrum antibacterial activity, while compounds 7a, 7c, 8b, 8d and 8e were active against the tested Gram-positive bacteria. The in vivo oral hypoglycemic activity of the new compounds was carried on streptozotocin (STZ)-induced diabetic rats. Compounds 7a, 8ab, and 8b produced potent dose-independent reduction of serum glucose levels, compared to the potent hypoglycemic drug gliclazide.

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Chapter 5. 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors in Development

Cited by 7 publications

References 78 publications

Antimicrobial and Hypoglycemic Activities of Novel N-Mannich Bases Derived from 5-(1-Adamantyl)-4-substituted-1,2,4-triazoline-3-thiones

Antimicrobial and Hypoglycemic Activities of Novel N-Mannich Bases Derived from 5-(1-Adamantyl)-4-substituted-1,2,4-triazoline-3-thiones

Structural Insights and Docking Analysis of Adamantane-Linked 1,2,4-Triazole Derivatives as Potential 11β-HSD1 Inhibitors

Adamantane-Isothiourea Hybrid Derivatives: Synthesis, Characterization, In Vitro Antimicrobial, and In Vivo Hypoglycemic Activities

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