The discovery of potent inhibitors of aldosterone synthase that exhibit selectivity over 11-β-hydroxylase

Adams, Christopher M.; Hu, Chii-Whei; Jeng, Arco Y.; Karki, Rajeshri G.; Ksander, Gary M.; LaSala, Dan; Leung-Chu, Jennifer; Liang, Guiqing; Liu, Qian; Meredith, Erik; Rao, Chang; Rigel, Dean F.; Shi, Jie; Smith, Sherri; Springer, Clayton; Zhang, Chun

doi:10.1016/j.bmcl.2010.06.086

Cited by 12 publications

(12 citation statements)

References 19 publications

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“…2). 24 Potent enzyme inhibition by the lead compound 5 was offset by a short HLM t 1/2 due to extensive metabolism on the isobutyl group by CYP enzymes. To mitigate the liability, the isobutyl group in 5 was replaced with an oxetane ring to yield 6, which demonstrated a greater than 10-fold increase in metabolic stability, while retaining aldosterone synthase inhibitory activity.…”

Section: Metabolism-guided Drug Designmentioning

confidence: 99%

Metabolism-guided drug design

et al. 2013

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Section: Metabolism-guided Drug Designmentioning

confidence: 99%

Metabolism-guided drug design

et al. 2013

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“…28 Analogue 3 had IC 50 < 10 nM, but the isobutyl group was heavily metabolized. To mitigate this metabolism, the isobutyl group was replaced with a substituted oxetane (4), a compound with a more than 10-fold increase in metabolic stability.…”

Section: ■ Saturated Heterocyclesmentioning

confidence: 99%

Mitigating Heterocycle Metabolism in Drug Discovery

2012

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In the past few decades, drug metabolism research has played an ever increasing role in the design of drugs. 1−3 In vitro metabolism assays 4 have become an integral part of the routine profiling of compounds made in drug discovery. 5 The data from these assays have allowed medicinal chemists to focus their efforts on compounds with improved metabolic stability. 6 Detailed metabolite identification studies are also done more routinely, which provide information on how to strategically replace or block metabolically labile sites. 7 Additionally, in vivo PK studies are regularly conducted in drug discovery, which helps to build in vitro−in vivo PK relationships. 4 The positive influence that these advances in PKDM sciences have had on drug discovery is reflected in the fact that fewer drug candidates fail in the clinic for PKDM related issues. 8 This suggests that medicinal chemists are successfully integrating the data generated by their PKDM colleagues into the design of compounds with fewer metabolic liabilities.Extensive data from metabolism studies have allowed medicinal chemists to develop general principles for reducing compound metabolism. These methods include, but are not limited to, reducing lipophilicity, altering sterics and electronics, introducing a conformational constraint, and altering the stereochemistry of their compounds. While no single method is able to solve every metabolic problem, these principles do give medicinal chemists guidance on how to improve the metabolic liabilities of their compounds. If the specific site of metabolism is known, medicinal chemists block the site, typically with a fluorine, or replace the metabolically labile group with a bioisostere. 9 While several authors have reviewed these techniques for reducing metabolism, 5,10,11 there is no review that summarizes different approaches to improving the metabolic stability of heterocycles. In this review, we summarize examples where changes were made at or near the heterocycle to improve metabolic stability. By summarizing these examples, we hope to provide a useful guide to medicinal chemists as they attempt to improve the metabolic profile of their own heterocyclic compounds.The majority of the examples that are included in this review came from searching the online open access database CHEMBL. 12 In addition to having pharmacology data on compounds from the medicinal chemistry literature, CHEMBL has over 120 000 points of data on the ADMET properties of compounds. With the help of the visualization software Spotfire, we were able to cull examples from the CHEMBL ADMET data that focused on heterocycles. We also identified examples from papers that cite leading reviews in the drug metabolism field 13−18 and were present in other recent reviews on drug metabolism. 19−22 The main criteria that we placed on the examples selected for this review was that the change made to improve metabolism had to occur at or near the heterocycle and nowhere else on the molecule. This allowed us to eliminate examples where a change made t...

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“…Therefore, the activity cut-off for active compounds of the test set was an IC 50 of less than 2 μM and for inactive compounds, it was more than 100 μM, respectively. Finally, a test set of 386 active compounds (Dorr et al, 1984 ; Ulmschneider et al, 2005a , b , 2006 ; Voets et al, 2005 , 2006 ; Heim et al, 2008 ; Lucas et al, 2008a , b , 2011 ; Adams et al, 2010 ; Roumen et al, 2010 ; Hille et al, 2011a , b ; Stefanachi et al, 2011 ; Zimmer et al, 2011 ; Hu et al, 2012 ; Yin et al, 2012 , 2013 ; Blass, 2013a , b ; Emmerich et al, 2013 ; Ferlin et al, 2013 ; Gobbi et al, 2013 ; Meredith et al, 2013 ; Pinto-Bazurco Mendieta et al, 2013 ) was collected for the theoretical validation of the models. This data set contained compounds with IC 50 s from 0.1 nM to 2 μM.…”

Section: Workflowmentioning

confidence: 99%

Pharmacophore Modeling and in Silico/in Vitro Screening for Human Cytochrome P450 11B1 and Cytochrome P450 11B2 Inhibitors

et al. 2017

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Cortisol synthase (CYP11B1) is the main enzyme for the endogenous synthesis of cortisol and its inhibition is a potential way for the treatment of diseases associated with increased cortisol levels, such as Cushing's syndrome, metabolic diseases, and delayed wound healing. Aldosterone synthase (CYP11B2) is the key enzyme for aldosterone biosynthesis and its inhibition is a promising approach for the treatment of congestive heart failure, cardiac fibrosis, and certain forms of hypertension. Both CYP11B1 and CYP11B2 are structurally very similar and expressed in the adrenal cortex. To facilitate the identification of novel inhibitors of these enzymes, ligand-based pharmacophore models of CYP11B1 and CYP11B2 inhibition were developed. A virtual screening of the SPECS database was performed with our pharmacophore queries. Biological evaluation of the selected hits lead to the discovery of three potent novel inhibitors of both CYP11B1 and CYP11B2 in the submicromolar range (compounds 8–10), one selective CYP11B1 inhibitor (Compound 11, IC50 = 2.5 μM), and one selective CYP11B2 inhibitor (compound 12, IC50 = 1.1 μM), respectively. The overall success rate of this prospective virtual screening experiment is 20.8% indicating good predictive power of the pharmacophore models.

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The discovery of potent inhibitors of aldosterone synthase that exhibit selectivity over 11-β-hydroxylase

Cited by 12 publications

References 19 publications

Metabolism-guided drug design

Metabolism-guided drug design

Mitigating Heterocycle Metabolism in Drug Discovery

Pharmacophore Modeling and in Silico/in Vitro Screening for Human Cytochrome P450 11B1 and Cytochrome P450 11B2 Inhibitors

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