Metabolism of MRX-I, a Novel Antibacterial Oxazolidinone, in Humans: The Oxidative Ring Opening of 2,3-Dihydropyridin-4-One Catalyzed by Non-P450 Enzymes

Ji, Meng; Zhong, Dafang; Li, Liang; Yuan, Zhengqiu; Yuan, Hong; Xie, Cen; Zhou, Jian; Li, Chen; Gordeev, M. F.; Liu, Jinqian; Chen, Xiaoyan

doi:10.1124/dmd.114.061747

Cited by 49 publications

(38 citation statements)

References 15 publications

(14 reference statements)

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“…For molecule 13 a “hypothesized glucuronide” is reported, an atypical N ‐glucuronide adduct to a pyridine ring. Molecules 18 and 23 show isoxazole ring cleavages. Compound 12 undergoes glucuronidation and sulfation after Ar−O−Ar ether cleavage (no examples in the training data) and molecule 14 undergoes the “unusual N‐acetylation of an aliphatic amine”.…”

Section: Resultsmentioning

confidence: 99%

MetScore: Site of Metabolism Prediction Beyond Cytochrome P450 Enzymes

Finkelmann

Goldmann²,

Schneider

et al. 2018

ChemMedChem

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The metabolism of xenobiotics by humans and other organisms is a complex process involving numerous enzymes that catalyze phase I (functionalization) and phase II (conjugation) reactions. Herein we introduce MetScore, a machine learning model that can predict both phase I and phase II reaction sites of drugs in a single prediction run. We developed cheminformatics workflows to filter and process reactions to obtain suitable phase I and phase II data sets for model training. Employing a recently developed molecular representation based on quantum chemical partial charges, we constructed random forest machine learning models for phase I and phase II reactions. After combining these models with our previous cytochrome P450 model and calibrating the combination against Bayer in-house data, we obtained the MetScore model that shows good performance, with Matthews correlation coefficients of 0.61 and 0.76 for diverse phase I and phase II reaction types, respectively. We validated its potential applicability to lead optimization campaigns for a new and independent data set compiled from recent publications. The results of this study demonstrate the usefulness of quantum-chemistry-derived molecular representations for reactivity prediction.

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Section: Resultsmentioning

confidence: 99%

MetScore: Site of Metabolism Prediction Beyond Cytochrome P450 Enzymes

Finkelmann

Goldmann²,

Schneider

et al. 2018

ChemMedChem

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“…MRX-I from MicuRx Pharmaceuticals Inc. is a further 2 nd -generation oxazolidinone with a 2,3-dihydropyridin-4-one (DHPO) ring replacing the morpholine ring found in linezolid [13]. It is active against methicillin-resistant Staphylococcus epidermidis , other coagulase-negative staphylococci, and MRSA [14, 15].…”

Section: Investigational Antibiotics Against Mrsamentioning

confidence: 99%

Investigational drugs to treat methicillin-resistantStaphylococcus aureus

Vuong

Yeh

Cheung

et al. 2015

Expert Opinion on Investigational Drugs

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Introduction Staphylococcus aureus remains one of the leading causes of morbidity and mortality worldwide. This is to a large extent due to antibiotic-resistant strains, in particular methicillin-resistant S. aureus (MRSA). While the toll of invasive MRSA infections appears to decrease in U.S. hospitals, the rate of community-associated MRSA infections remains constant and there is a surge of MRSA in many other countries. This situation calls for continuing if not increased efforts to find novel strategies to combat MRSA infections. Areas covered This review will provide an overview of current investigational antibiotics in clinical development (up to phase II), and of therapeutic antibodies and alternative drugs against S. aureus in preclinical and clinical development, including a short description of the mechanism of action and a presentation of microbiological and clinical data. Expert opinion Increased recent antibiotic development efforts and results from pathogenesis research have led to several new antibiotics and alternative drugs, as well as a more informed selection of targets for vaccination efforts against MRSA. This developing portfolio of novel anti-staphylococcal drugs will hopefully provide us with additional and more efficient ways to combat MRSA infections in the near future and prevent us from running out of treatment options, even if new resistances arise.

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“…FMO5 differs markedly from FMOs 1, 2, and 3 with respect to its substrate specificities ( Phillips and Shephard, 2017 ). Although FMO5 catalyzes the N -oxygenation of short-chain aliphatic primary amines such as N -octylamine ( Overby et al, 1995 ) and the S -oxygenation of S -methyl-esonarimod, an active metabolite of the antirheumatic agent esonarimod ( Ohmi et al, 2003 ; Zhang et al, 2007 ), it is apparently more efficient in catalyzing the oxygenation of a variety of carbonyl compounds, via a Baeyer-Villiger process ( Fiorentini et al, 2016 ), including the anticancer drug E7016 ( Lai et al, 2011 ) and the antibacterial agent MRX-I ( Meng et al, 2015 ). FMOs 1, 2, and 3 ( Siddens et al, 2014 ) and FMO5 ( Fiorentini et al, 2016 ) can act also as NADPH oxidases, producing hydrogen peroxide.…”

Section: Introductionmentioning

confidence: 99%

Identification of Flavin-Containing Monooxygenase 5 (FMO5) as a Regulator of Glucose Homeostasis and a Potential Sensor of Gut Bacteria

et al. 2017

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We have previously identified flavin-containing monooxygenase 5 (FMO5) as a regulator of metabolic aging. The aim of the present study was to investigate the role of FMO5 in glucose homeostasis and the impact of diet and gut flora on the phenotype of mice in which the Fmo5 gene has been disrupted (Fmo5−/− mice). In comparison with wild-type (WT) counterparts, Fmo5−/− mice are resistant to age-related changes in glucose homeostasis and maintain the higher glucose tolerance and insulin sensitivity characteristic of young animals. When fed a high-fat diet, they are protected against weight gain and reduction of insulin sensitivity. The phenotype of Fmo5−/− mice is independent of diet and the gut microbiome and is determined solely by the host genotype. Fmo5−/− mice have metabolic characteristics similar to those of germ-free mice, indicating that FMO5 plays a role in sensing or responding to gut bacteria. In WT mice, FMO5 is present in the mucosal epithelium of the gastrointestinal tract where it is induced in response to a high-fat diet. In comparison with WT mice, Fmo5−/− mice have fewer colonic goblet cells, and they differ in the production of the colonic hormone resistin-like molecule β. Fmo5−/− mice have lower concentrations of tumor necrosis factor α in plasma and of complement component 3 in epididymal white adipose tissue, indicative of improved inflammatory tone. Our results implicate FMO5 as a regulator of body weight and of glucose disposal and insulin sensitivity and, thus, identify FMO5 as a potential novel therapeutic target for obesity and insulin resistance.

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Metabolism of MRX-I, a Novel Antibacterial Oxazolidinone, in Humans: The Oxidative Ring Opening of 2,3-Dihydropyridin-4-One Catalyzed by Non-P450 Enzymes

Cited by 49 publications

References 15 publications

MetScore: Site of Metabolism Prediction Beyond Cytochrome P450 Enzymes

MetScore: Site of Metabolism Prediction Beyond Cytochrome P450 Enzymes

Investigational drugs to treat methicillin-resistantStaphylococcus aureus

Identification of Flavin-Containing Monooxygenase 5 (FMO5) as a Regulator of Glucose Homeostasis and a Potential Sensor of Gut Bacteria

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