Lead Optimization Generates CYP11B1 Inhibitors of Pyridylmethyl Isoxazole Type with Improved Pharmacological Profile for the Treatment of Cushing’s Disease

Emmerich, Juliette; Koppen, Chris J. van; Burkhart, Jens L.; Hu, Qingzhong; Siebenbürger, Lorenz; Boerger, Carsten; Scheuer, Cláudia; Laschke, Matthias W.; Menger, Michael D.; Hartmann, Rolf W.

doi:10.1021/acs.jmedchem.7b00437

Cited by 23 publications

(17 citation statements)

References 45 publications

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“…Estrogens control female development and fertility but can promote breast cancer proliferation, and selective inhibitors of CYP19A1 treat estrogen-responsive breast cancer (10). Selective inhibitors of CYP11B1 or CYP11B2 are of similar clinical interest (11)(12)(13)(14)(15)(16)(17) for Cushing's disease and hypertension. The development of such inhibitors has been impeded by the 93% amino acid sequence identity between them and their similar steroid-binding functionality.…”

mentioning

confidence: 99%

Structure of human cortisol-producing cytochrome P450 11B1 bound to the breast cancer drug fadrozole provides insights for drug design

Brixius‐Anderko

Scott

2019

Journal of Biological Chemistry

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mentioning

confidence: 99%

Structure of human cortisol-producing cytochrome P450 11B1 bound to the breast cancer drug fadrozole provides insights for drug design

Brixius‐Anderko

Scott

2019

Journal of Biological Chemistry

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“…Separation and measurement of the substrate and product were accomplished by radio HPLC. Metabolic stabilities in human, mouse, and rat liver S9 fractions were determined in the presence of the cofactors NADP, uridine diphosphate glucuronic acid (UDPGA), and PAPS, as described earlier. ,,− The cellular h 17β-HSD2 inhibitory activity of compounds was measured using the breast cancer cell-line MDA-MB-231 (having negligible 17β-HSD1 activity) with 200 nM [ 3 H]-E2 as the substrate and incubated for 6 h at 37 °C . After ether extraction, the substrate and product were separated and measured as described above.…”

Section: Methodsmentioning

confidence: 99%

“…After ether extraction, the substrate and product were separated and measured as described above. MTT cell viability assays in human embryonic kidney 293 cells were performed as described previously. , ERα agonistic and antagonistic activity of the compounds (0.1, 1.0, and 10 μM) were tested in a luciferase assay with U2OS cells transfected with 2xERE-tk-luc plasmid, in triplicate in three independent experiments as described before. , E2 concentration in the antagonistic ERα luciferase assay was 1.0 nM.…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, and Biological Characterization of Orally Active 17β-Hydroxysteroid Dehydrogenase Type 2 Inhibitors Targeting the Prevention of Osteoporosis

et al. 2019

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Osteoporosis is predominantly treated with drugs that inhibit further bone resorption due to estrogen deficiency. Yet, osteoporosis drugs that not only inhibit bone resorption but also stimulate bone formation, such as potentially inhibitors of 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2), may be more efficacious in the treatment of osteoporosis. Blockade of 17β-HSD2 is thought to increase intracellular estradiol and testosterone in bone, thereby inhibiting bone resorption by osteoclasts and stimulating bone formation by osteoblasts, respectively. We here describe the design, synthesis, and biological characterization of a novel bicyclic-substituted hydroxyphenylmethanone 17β-HSD2 inhibitor (compound 24). Compound 24 is a nanomolar potent inhibitor of human 17β-HSD2 (IC50 of 6.1 nM) and rodent 17β-HSD2 with low in vitro cellular toxicity, devoid of detectable estrogen receptor α affinity, displays high aqueous solubility and in vitro metabolic stability, and has an excellent oral pharmacokinetic profile for testing in a rat osteoporosis model. Administration of 24 in a rat osteoporosis model demonstrates its bone-sparing efficacy.

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“…An ideal drug would inhibit only the lyase step and not the hydroxylation, but this may not be feasible with an active site that must accommodate both a substrate and an inhibitor. A number of drugs, including mifepristone (Chu et al, 2001), have been used to inhibit adrenal P450 11B1 in treating Cushing's disease, which is a syndrome involving overproduction of cortisol (Boscaro et al, 2000;Yin et al, 2012;Emmerich et al, 2013Emmerich et al, , 2017.…”

Section: Label As Non-inhibitormentioning

confidence: 99%

Inhibition of Cytochrome P450 Enzymes by Drugs-Molecular Basis and Practical Applications

Guengerich

2022

Biomol Ther (Seoul)

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Drug-drug interactions are important and accordingly are a major issue in the advancement of new chemical entities to patients. In one study (Montané et al., 2018), drug-related deaths accounted for 7% of all deaths in hospital settings. Drug-drug interactions are an issue in this regard. Although some pharmacodynamic issues are involved, a large fraction of the drug-drug interactions is pharmacokinetic in nature.A general overview of the interactions of a chemical with an enzyme is shown in Fig. 1A, where an enzyme involved in the metabolism of a drug is considered. The drug is converted to a product, often called a metabolite. With respect to the parent drug molecule, the product may have unaltered pharmacological activity, lose some or all of its pharmacological activity, be even more active, or be toxic. In the interactions of two drugs, one is sometimes termed the "perpetrator" and one the "victim" (Fig. 1B). In some cases, drug interaction due to enhanced metabolism by induction or allosteric activation may be seen and have clinical consequences (Bolt et al., 1977), but the focus here will be on competitive and irreversible inhibitors that attenuate drug metabolism (as "perpetrators").Recently Yu et al. (2018) evaluated drug-drug interactions in 103 recent drug approvals by the United States Food and Drug Administration (FDA). Of these, 45 were involved as victims (substrates) in interactions with marketed drugs (perpetrators). The therapeutic classes are shown in Fig. 2A, with cancer treatments accounting for more than 1/4. The enzymes involved are primarily cytochrome P450 and transporter enzymes (Fig. 2B), with P450 3A4/5 involved in ~2/3 of the interactions. Of the 103 new drugs, 20 were acting as perpetrators to some extent (Yu et al., 2018), with P450 3A4/5 and P-glycoprotein again being the most prominent enzymes (Fig. 1B). Accordingly, this review will focus on issues of inhibition of P450 3A4 (In general P450 3A4 and 3A5 have similar substrate specificity and are sensitive to the same inhibitors, with some important exceptions (Hardy et al., 2014;Zhu et al., 2014;Kramlinger et al., 2015), but many experiments with drugs were done only with P450 3A4-or 3A4 and 3A5 were not discriminated-and will be referred to as 3A4 in that context). BACKGROUND ON P450SP450s enzymes are the main catalysts involved in the oxidation of chemicals in general (Rendic and Guengerich, 2015), including drugs. The same is true for involvement in Please cite this article in press as: Guengerich, Inhibition of Cytochrome P450 Enzymes by Drugs-Molecular Basis and Practical Applications, Biomol. Ther.

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Lead Optimization Generates CYP11B1 Inhibitors of Pyridylmethyl Isoxazole Type with Improved Pharmacological Profile for the Treatment of Cushing’s Disease

Cited by 23 publications

References 45 publications

Structure of human cortisol-producing cytochrome P450 11B1 bound to the breast cancer drug fadrozole provides insights for drug design

Structure of human cortisol-producing cytochrome P450 11B1 bound to the breast cancer drug fadrozole provides insights for drug design

Design, Synthesis, and Biological Characterization of Orally Active 17β-Hydroxysteroid Dehydrogenase Type 2 Inhibitors Targeting the Prevention of Osteoporosis

Inhibition of Cytochrome P450 Enzymes by Drugs-Molecular Basis and Practical Applications

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