Novel Cytochrome P450-Mediated Ring Opening of the 1,3,4-Oxadiazole in Setileuton, a 5-Lipoxygenase Inhibitor

Maciolek, Cheri M; Ma, Bennett; Menzel, Karsten; Laliberté, Sébastien; Bateman, Kevin P.; Krolikowski, Paul; Gibson, Christopher R

doi:10.1124/dmd.110.037366

Cited by 13 publications

(23 citation statements)

References 24 publications

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“…In the COPD study, MK‐0633 was not significantly more effective than placebo, although the AST and ALT levels in this study were not elevated . The clinical inefficacy might be due to the CYP450‐mediated formation of an 1,3,4‐oxadiazole ring‐opened metabolite which might be inactive. Further improvement aiming at a metabolically more stable compound led to derivative MK‐4413 whose clinical efficacy needs to be evaluated.…”

Section: Current Clinical Development Status Of Novel 5‐lipoxygenase mentioning

confidence: 54%

Recent Advances in the Search for Novel 5‐Lipoxygenase Inhibitors

Steinhilber

Hofmann

2013

Basic Clin Pharma Tox

117

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5-Lipoxygenase (5-LO) is an important enzyme of the arachidonic acid cascade and catalyses with the help of FLAP, the 5-LO-activating protein, the formation of bioactive leukotrienes (LTs). LTs are inflammatory mediators playing a pathophysiological role in different diseases such as asthma, allergic rhinitis as well as cardiovascular diseases and certain types of cancer. Up to now, only one 5-LO inhibitor is on the market, zileuton for the treatment of asthma. With the rising number of indications for anti-LT therapy, 5-LO inhibitor drug development becomes more and more important. This MiniReview gives an update on 5-LO inhibitors currently under clinical development. Furthermore, the recent advances in the search for novel 5-lipoxygenase inhibitors with a focus on computational methods are summarized. Currently, licofelone is the compound with the highest clinical development status (completed phase III trials). 5-LO inhibitor screening programmes based on computational methods could deliver several promising drug-like new molecules. These activities can be expected to be driven by the newly resolved structure of human 5-LO in the future, enabling structure-based drug design. For the prospective drugs in late-stage clinical development, the future will show their clinical safety and efficacy in the particular diseases. The 5-LO-derived arachidonic acid metabolites have been shown to be potent mediators of inflammatory reactions. During the last decades, many investigations demonstrated that the 5-LO pathway plays a role in the development of allergic diseases such as asthma [2] Most of the 5-LO inhibitors bind to the catalytic site and show a more or less competitive inhibition of the enzyme. 5-LO inhibitors can be classified into three main groups: redoxactive compounds, iron-ligand inhibitors with weak redoxactive properties and non-redox-type inhibitors [7].Insights into the pharmacological potential of 5-LO inhibitors were obtained in studies using 5-LO-deficient mice. 5-LOdeficient mice are strongly resistant against PAF-induced shock and show reduced airway reactivity [8]. Furthermore, interference with the 5-LO pathway via blockage of FLAP was found to reduce collagen-induced arthritis [9]. Another study with 5-LO-deficient mice suggests that 5-LO plays a critical role in the development of chronic myeloid leukaemia [4].Up to now, the iron-ligand type-5-LO inhibitor zileuton is the only 5-LO inhibitor that came on the market for the treatment of asthma. So, how to come up with novel inhibitors? There are several different strategies in drug design, divided mainly in (I) the improvement of already known compounds by medicinal chemistry approaches to cope with, for example, a poor pharmacokinetic profile and (II) the identification of novel scaffolds. For the latter, high-throughput screening of large databases of synthetic compounds or natural product extracts to find active compounds can be applied. Alternatively, computational methods are quite helpful tools to speed up the drug discovery p...

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Section: Current Clinical Development Status Of Novel 5‐lipoxygenase mentioning

confidence: 54%

Recent Advances in the Search for Novel 5‐Lipoxygenase Inhibitors

Steinhilber

Hofmann

2013

Basic Clin Pharma Tox

117

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“…Compound 105 is more polar than analogue 104 , which may explain the improvement in metabolic stability. Also, if the five-membered ring on compound 104 is the site of metabolism, the 1,2,4-oxadiazole ring may undergo metabolic N–O ring-opening, which is precedented in the literature. , Without an N–O bond, the 1,3,4-oxadiazole ring on 105 would not undergo this route of metabolism …”

Section: Heteroaromatic Compoundsmentioning

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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“…The mass detector was operated in the electron-impact ionization mode (ionization energy, 70 eV). Molecular ion peaks were identified and possible structures were drawn on the basis of already reported data on decomposition pattern/chemical reactions of functional groups in OXCPM (14)(15)(16)(17)(18)(19).…”

Section: Identification Of Degradation Productsmentioning

confidence: 99%

Reverse-Phase Chromatographic Determination and Intrinsic Stability Behavior of 5-[(4-Chlorophenoxy)Methyl]-1,3,4-Oxadiazole-2-Thiol

et al. 2018

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The study describes the development and preliminary validation of a simple reverse-phase chromatographic method for determination of a novel drug candidate, 5-[(4-chlorophenoxy) methyl]-1,3,4-oxadiazole-2-thiol (OXCPM), in bulk and stressed solution, in order to find out the intrinsic stability behavior of the compound. Isocratic elution was carried out at a flow rate of 1.0 mL min-1 through a Promosil C18 column maintained at 25 °C, using the mobile phase comprising acetonitrile and aqueous o-H3PO4 (pH 2.67) (1:1, V/V). Detection was performed at 258 nm. The response of the detector was linear in a concentration range of 1.25-50.00 μg mL-1 with the correlation coefficient of 0.9996 ± 0.0001. Cumulative intra-day, inter-day and inter-instrument accuracy (99.5 ± 1.0, 100.2 ± 1.0 and 100.3 ± 0.4 %, resp.) with RSD less than 5 % indicated that the method was accurate and precise. The resolution and selectivity factor (>2 and >1, resp.), particularly in copper metal- and dry-heat-stress solutions, depicted the selectivity of the method. OXCPM remained stable under hydrolytic (acidic and neutral pH, ≤ 37 °C), photolytic and moist heat stress conditions. Under alkaline conditions (hydrolytic and photolytic), polar products were formed that eluted very fast through the column (tR < 3.75 min). At room temperature, the compound was susceptible to oxidation by hydrogen peroxide and transition metals. The ionogram of most of the stress solutions indicated the presence of a product having m/z 256, which might be a result of N- or Smethylation or -SH oxidation. The results of the study indicate that the method is selective, sensitive and suitable to be used for determination of OXCPM in bulk and under stress conditions.

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Novel Cytochrome P450-Mediated Ring Opening of the 1,3,4-Oxadiazole in Setileuton, a 5-Lipoxygenase Inhibitor

Cited by 13 publications

References 24 publications

Recent Advances in the Search for Novel 5‐Lipoxygenase Inhibitors

Recent Advances in the Search for Novel 5‐Lipoxygenase Inhibitors

Mitigating Heterocycle Metabolism in Drug Discovery

Reverse-Phase Chromatographic Determination and Intrinsic Stability Behavior of 5-[(4-Chlorophenoxy)Methyl]-1,3,4-Oxadiazole-2-Thiol

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