Discovery of HSD-621 as a Potential Agent for the Treatment of Type 2 Diabetes

Wan, Zhengming; Chenail, Eva; Li, Huan‐Qiu; Ipek, Manus; Xiang, Jason; Suri, Vipin; Hahm, Seung; Bard, Joel; Svenson, Kristine; Xu, Xin; Tian, Xianbin; Wang, Mengmeng; Li, Xiangping; Johnson, Christian E.; Qadri, Ariful; Panza, Darrell; Perreault, Mylène; Mansour, Tarek S.; Tobin, James F.; Saiah, Eddine

doi:10.1021/ml300352x

Cited by 16 publications

(6 citation statements)

References 38 publications

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“…These and other preclinical findings build a strong case that inhibition of 11β-HSD1 may be an efficacious approach for the treatment of metabolic syndrome. As a result, much attention has been focused on the discovery and development of inhibitors of this enzyme. − In clinical trials, Incyte, Merck, and others have demonstrated that 11β-HSD1 inhibitors improved glycaemic control, lipid profiles, and blood pressure with modest weight loss . In addition to this indication, we recently explored and proposed atheroprotection as an emerging indication for this target.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Clinical Candidate 2-((2S,6S)-2-Phenyl-6-hydroxyadamantan-2-yl)-1-(3′-hydroxyazetidin-1-yl)ethanone [BMS-816336], an Orally Active Novel Selective 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor

Chen

et al. 2017

J. Med. Chem.

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BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme (IC 3.0 nM) with >10000-fold selectivity over human 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED 0.12 mg/kg) and in DIO mice. It is orally bioavailable (%F ranges from 20 to 72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans. This ADME profile met our selection criteria for once daily administration, targeting robust inhibition of 11β-HSD1 enzyme for the first 12 h period after dosing followed by an "inhibition holiday" so that the potential for hypothalamic-pituitary-adrenal (HPA) axis activation might be mitigated. 6n-2 was found to be well-tolerated in phase 1 clinical studies and represents a potential new treatment for type 2 diabetes, metabolic syndrome, and other human diseases modulated by glucocorticoid control.

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Section: Introductionmentioning

confidence: 99%

Discovery of Clinical Candidate 2-((2S,6S)-2-Phenyl-6-hydroxyadamantan-2-yl)-1-(3′-hydroxyazetidin-1-yl)ethanone [BMS-816336], an Orally Active Novel Selective 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor

Chen

et al. 2017

J. Med. Chem.

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“…The group of non-steroidal 11β-HSD1 inhibitors includes, inter alia, 4-substituted 2-aminothiazole derivatives: Biovitrum BVT-2733, Biovitrum BVT-14225 and Biovitrum BVT-3498 [ 24 , 25 , 26 , 27 ] and highly selective 2-aminothiazol-4(5 H )-es: Amgen 2922 and AMG-221 (BVT-83370) [ 24 , 28 , 29 , 30 ]. In the case of the 11β-HSD2 isoform, the CBX diastereoisomer (18α-glycyrrhetinic acid 3β- O -hemisuccinate, αCBX) is an effective inhibitor [ 31 ], whereas, among the non-steroidal inhibitors, antifungal drugs: itraconazole and posaconazole, which are the triazole derivatives, can be mentioned Scheme 2 ) [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Novel 2-(Isopropylamino)thiazol-4(5H)-one Derivatives and Their Inhibitory Activity of 11β-HSD1 and 11β-HSD2 in Aspect of Carcinogenesis Prevention

et al. 2020

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Glucocorticoid metabolism at the tissue level is regulated by two isoenzymes 11β-hydroxysteroid dehydrogenase (11β-HSD), which mutually convert biologically active cortisol and inactive cortisone. Recent research is focused on the role of 11β-HSD1 and 11β-HSD2 as autocrine factors of tumor cell proliferation and differentiation. Herein, we report the synthesis of novel 2-(isopropylamino)thiazol-4(5H)-one derivatives and their inhibitory activity for 11β-HSD1 and 11β-HSD2. The derivative containing the spiro system of thiazole and cyclohexane rings shows the highest degree of 11β-HSD1 inhibition (54.53% at 10 µM) and is the most selective inhibitor of this enzyme among the tested compounds. In turn, derivatives containing ethyl and n-propyl group at C-5 of thiazole ring inhibit the activity of 11β-HSD2 to a high degree (47.08 and 54.59% at 10 µM respectively) and are completely selective. Inhibition of the activity of these enzymes may have a significant impact on the process of formation and course of tumors. Therefore, these compounds can be considered as potential pharmaceuticals supporting anti-cancer therapy.

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“…5 Extensive efforts have been pursued to develop 11β-HSD1 inhibitors as a potential treatment of type 2 diabetes from multiple groups. 6 Phase-I results were reported for 1 PF-00915275, 7 2 HSD-016, 8 3 HSD-621, 9 4 AMG221, 10 and 5 AZD8329. 11 Phase-II trials were conducted for INCB13739 (structure not disclosed) 12 and 6 MK-0916.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Potent Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 Using a Novel Growth-Based Protocol of in Silico Screening and Optimization in CONTOUR

Liu

Singh²,

Zheng

et al. 2019

J. Chem. Inf. Model.

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With the continuous progress in ultralarge virtual libraries which are readily accessible, it is of great interest to explore this large chemical space for hit identification and lead optimization using reliable structure-based approaches. In this work, a novel growth-based screening protocol has been designed and implemented in the structure-based design platform CONTOUR. The protocol was used to screen the ZINC database in silico and optimize hits to discover 11β-HSD1 inhibitors. In contrast to molecular docking, the virtual screening process makes significant improvements in computational efficiency without losing chemical equities through partitioning 1.8 million ZINC compounds into fragments, docking fragments to form key hydrogen bonds with anchor residues, reorganizing molecules into molecular fragment trees using matched fragments and common substructures, and then regrowing molecules with the help of developed intelligent growth features inside the protein binding site to find hits. The growth-base screening approach is validated by the high hit rate. A total of 50 compounds have been selected for testing; of these, 15 hits having diverse scaffolds are found to inhibit 11β-HSD1 with IC50 values of less than 1 μM in a biochemical enzyme assay. The best hit which exhibits an enzyme IC50 of 33 nM is further developed to a novel series of bicyclic 11β-HSD1 inhibitors with the best inhibition of enzyme IC50 of 3.1 nM. The final lead candidate exhibits IC50 values of 7.2 and 21 nM in enzyme and adipocyte assays, respectively, displayed greater than 1000-fold of selectivity over 11β-HSD2 and two other related hydroxysteroid dehydrogenases, and can serve as good starting points for further optimization to develop clinical candidates.

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Discovery of HSD-621 as a Potential Agent for the Treatment of Type 2 Diabetes

Cited by 16 publications

References 38 publications

Discovery of Clinical Candidate 2-((2S,6S)-2-Phenyl-6-hydroxyadamantan-2-yl)-1-(3′-hydroxyazetidin-1-yl)ethanone [BMS-816336], an Orally Active Novel Selective 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor

Discovery of Clinical Candidate 2-((2S,6S)-2-Phenyl-6-hydroxyadamantan-2-yl)-1-(3′-hydroxyazetidin-1-yl)ethanone [BMS-816336], an Orally Active Novel Selective 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor

Synthesis of Novel 2-(Isopropylamino)thiazol-4(5H)-one Derivatives and Their Inhibitory Activity of 11β-HSD1 and 11β-HSD2 in Aspect of Carcinogenesis Prevention

Discovery of Potent Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 Using a Novel Growth-Based Protocol of in Silico Screening and Optimization in CONTOUR

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