Aurora Kinase Inhibitors Based on the Imidazo[1,2-<i>a</i>]pyrazine Core: Fluorine and Deuterium Incorporation Improve Oral Absorption and Exposure

Kerekes, Angela D.; Esposite, Sara; Doll, Ronald J.; Tagat, Jayaram R.; Yu, Tao; Xiao, Yuan; Zhang, Yonglian; Prelusky, Dan B.; Tevar, Seema; Gray, Kimberly; Terracina, Gaby A; Lee, Suining; Jones, Jennifer; Liu, Ming; Basso, Andrea; Smith, Elizabeth B.

doi:10.1021/jm1010995

Cited by 57 publications

(42 citation statements)

References 21 publications

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“…Rat PK of selected aurora kinase inhibitors. 34 All compounds had IC 50 at Aurora A and Aurora B of ≤4 and ≤13 nM, respectively. The po AUC was determined in SD rats from 0−6 h after a 10 mg/kg oral dose.…”

Section: ■ Saturated Heterocyclesmentioning

confidence: 97%

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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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Section: ■ Saturated Heterocyclesmentioning

confidence: 97%

“…34 One of their more advanced compounds in the paper contained a 4-fluoropiperidine (24), which had a rat oral AUC of 2.2 μM·h. To further improve the PK, the 4,4-difluoro analogue (25) was prepared, but it had a lower rat oral AUC.…”

Section: ■ Saturated Heterocyclesmentioning

confidence: 99%

Mitigating Heterocycle Metabolism in Drug Discovery

2012

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“…103 However, this compound exhibited poor oral bioavailability in the rat due to a combination of poor absorption and rapid metabolism with the AUC reported as zero μM·h. Metabolite identification studies using radiolabeled material revealed that N-dealkylation of the amine moiety, which was known to project into solvent when bound to the enzyme, was the primary clearance pathway.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Applications of Fluorine in Medicinal Chemistry

et al. 2015

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The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, (18)F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in positron emission tomography.

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“…[1, 2] Thus the introduction of fluorine has been especially valuable in the process of drug discovery to fine tune many different target and off-target related properties. [3–6] For example, fluorine has been used to increase the binding affinity of small molecules to its target, [7] to tune the pK B and logD, [8] to improve target selectivity, [9] to improve oral absorption and exposure, [10] to prevent from metabolism [11] or to increase the antibacterial spectrum. [12] Not surprisingly, an estimated 20% of all pharmaceuticals contain fluorine.…”

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confidence: 99%