Structure–activity relationship study of EphB3 receptor tyrosine kinase inhibitors

Qiao, Lixin; Choi, Sung‐Woon; Case, April; Gainer, Thomas G.; Seyb, Kathleen; Glicksman, Marcie A.; Lo, Donald C.; Stein, Ross L.; Cuny, Gregory D.

doi:10.1016/j.bmcl.2009.09.010

Cited by 25 publications

(28 citation statements)

References 29 publications

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“…39 Their 1-substituted piperidine analogue 35 was significantly less stable in MLM than the analogue with the 4-substituted piperidine (36). This change in the position of the nitrogen lowered the cLogD 7.4 and produced an analogue with a more basic nitrogen, which may have contributed to the improvement in metabolic stability.…”

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%

“…Half-life and CL int were determined in MLM. 39 Figure 12. In vitro potency and RLM stability for selected human H4R inverse agonists.…”

Section: ■ Saturated Heterocyclesmentioning

confidence: 99%

Mitigating Heterocycle Metabolism in Drug Discovery

2012

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“…Synthesis of synthons 7aeg was achieved by condensation between the suitable aminopyridazine 6a [12] or aminopyridines 6bed [12,13] and the appropriate a-halogenocarbonyl compounds 5aec [12].…”

Section: Chemistrymentioning

confidence: 99%

“…The possible inversion of two values in the NMR spectra is expressed by an asterisk. Known compounds were prepared according to literature procedures: bromoketones 5aec [12], amines 6a and 6b [12], amine 6d [13], amine 9 [15], amine 13 [16], imidazoazines 1aeg, 2a, 2b, 2d, 2f, 2h, 2j, 2l, 2m, 7b, 7d, 8bed, 8feh and 8jem [12] and imidazo[1,2-a] pyridine 18 [17].…”

Section: General Remarksmentioning

confidence: 99%

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A small-molecule cell-based screen led to the identification of biphenylimidazoazines with highly potent and broad-spectrum anti-apicomplexan activity

Moine

Denevault‐Sabourin

Debierre‐Grockiego

et al. 2015

European Journal of Medicinal Chemistry

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Completing the structural family portrait of the human EphB tyrosine kinase domains

et al. 2014

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The EphB receptors have key roles in cell morphology, adhesion, migration and invasion, and their aberrant action has been linked with the development and progression of many different tumor types. Their conflicting expression patterns in cancer tissues, combined with their high sequence and structural identity, present interesting challenges to those seeking to develop selective therapeutic molecules targeting this large receptor family. Here, we present the first structure of the EphB1 tyrosine kinase domain determined by X-ray crystallography to 2.5Å . Our comparative crystalisation analysis of the human EphB family kinases has also yielded new crystal forms of the human EphB2 and EphB4 catalytic domains. Unable to crystallize the wild-type EphB3 kinase domain, we used rational engineering (based on our new structures of EphB1, EphB2, and EphB4) to identify a single point mutation which facilitated its crystallization and structure determination to 2.2 Å . This mutation also improved the soluble recombinant yield of this kinase within Escherichia coli, and increased both its intrinsic stability and catalytic turnover, without affecting its ligandbinding profile. The partial ordering of the activation loop in the EphB3 structure alludes to a potential cis-phosphorylation mechanism for the EphB kinases. With the kinase domain structures of all four catalytically competent human EphB receptors now determined, a picture begins to emerge of possible opportunities to produce EphB isozyme-selective kinase inhibitors for mechanistic studies and therapeutic applications.

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Structure–activity relationship study of EphB3 receptor tyrosine kinase inhibitors

Cited by 25 publications

References 29 publications

Mitigating Heterocycle Metabolism in Drug Discovery

Mitigating Heterocycle Metabolism in Drug Discovery

A small-molecule cell-based screen led to the identification of biphenylimidazoazines with highly potent and broad-spectrum anti-apicomplexan activity

Completing the structural family portrait of the human EphB tyrosine kinase domains

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