Hydantoin based inhibitors of MMP13—Discovery of AZD6605

Savi, Chris De; Waterson, David; Pape, Andrew R.; Lamont, Scott G.; Hadley, Elma; Mills, Mark; Page, Ken; Bowyer, Jonathan; Maciewicz, Rose A.

doi:10.1016/j.bmcl.2013.05.089

Cited by 20 publications

(18 citation statements)

References 26 publications

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“…At AstraZenaca, De Savi et al. developed hydantoin‐based inhibitors of MMP‐13 . They focused on replacing the hydroxamate or reverse hydroxamate zinc‐binding group found in early MMP inhibitors and optimizing the novel compounds with respect to potency, selectivity, and pharmacokinetic properties.…”

Section: Mmp Inhibitorsmentioning

confidence: 99%

“… Hydantoin‐based inhibitor 23 complexed to MMP‐13 (PDB ID: 4JPA; ligand carbon atoms are in green, the zinc(II) ion is a gray sphere, and the calcium(II) ion is a green sphere) …”

Section: Mmp Inhibitorsmentioning

confidence: 99%

“…The very long P1′ residue penetrates the S1′ pocket and points the nitrile group towards the selectivity loop present in MMP‐13. With an IC 50 value of 3.3 n m for MMP‐13, compared with >53 μ m for MMP‐14, compound 23 displayed very high selectivity …”

Section: Mmp Inhibitorsmentioning

confidence: 99%

“…[111] At AstraZenaca, De Savi et al developed hydantoin-based inhibitors of MMP-13. [112] They focusedo nr eplacing the hydroxamate or reverse hydroxamatez inc-binding group found in early MMP inhibitors ando ptimizing the novel compounds with respectt op otency,s electivity,a nd pharmacokinetic properties. Inhibitor 23 (Figures 15 and 17) engages in monodentate chelation to thec atalytic zinc(II) iona nd the hydrogen atom bound to the second nitrogen atom in the hydantoin ring forms ah ydrogen bond to the backbone amino acid Ala186.…”

Section: Other Zinc-binding Groupsmentioning

confidence: 99%

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Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

Fischer

Senn

Riedl

2019

Chemistry A European J

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Matrix metalloproteinases (MMPs) are involved in a multitude of severe diseases. Despite MMPs being considered druggable targets, past drug‐discovery programs have not delivered the anticipated clinical benefits. This review examines the latest structural evolution of small‐molecule inhibitors of MMPs, with a focus on the development of novel chemical entities with improved affinity and selectivity profiles. X‐ray crystallographic data of the protein targets and cocrystal structures with inhibitors proved to be key for the success achieved during this ambitious endeavor. An evolutionary view on the structural diversity generated for this class of molecules is provided. This encouraging development paves the way for the clinical utilization of this class of highly relevant therapeutic targets. The structure‐based design of superior MMP inhibitors highlights the power of this technique and displays strategies for the development of treatment options based on the modulation of challenging drug targets.

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Section: Mmp Inhibitorsmentioning

confidence: 99%

“… Hydantoin‐based inhibitor 23 complexed to MMP‐13 (PDB ID: 4JPA; ligand carbon atoms are in green, the zinc(II) ion is a gray sphere, and the calcium(II) ion is a green sphere) …”

Section: Mmp Inhibitorsmentioning

confidence: 99%

Section: Mmp Inhibitorsmentioning

confidence: 99%

Section: Other Zinc-binding Groupsmentioning

confidence: 99%

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Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

Fischer

Senn

Riedl

2019

Chemistry A European J

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“…Thus, hydantoin ( 6 ) derivatives are represented by approved drugs (Phenytoin, Fosphenytoin), pesticides (Imiprothrin, Iprodione), or inhibitors of matrix metalloproteinases (MMPs). 18 Thiohydantoin ( 7 ) derivatives have been identified as antimicrobials 19 and antitumor 20 agents with topoisomerase I inhibitory activities. 21 Rhodanine ( 8 ) derivatives are well known beta-lactamase inhibitors.…”

mentioning

confidence: 99%

Isatin derivatives with activity against apoptosis-resistant cancer cells

Evdokimov

Magedov

McBrayer

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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In a search of small molecules active against apoptosis-resistant cancer cells, a series of isatin-based heterocyclic compounds were synthesized and found to inhibit proliferation of cancer cell lines resistant to apoptosis. The synthesis of these compounds involved a condensation of commercially available, active methylene heterocycles with isatin proceeding in moderate to excellent yields. The heterocyclic scaffolds prepared in the current investigation appear to be a useful starting point for the development of agents to fight cancers with apoptosis resistance, and thus, associated with dismal prognoses.

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Tailor‐Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals

Mei

Han

White

et al. 2020

Chemistry A European J

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Structural analysis of modern pharmaceutical practices allows for the identification of two rapidly growing trends: the introduction of tailor‐made amino acids and the exploitation of fluorinated motifs. Curiously, the former represents one of the most ubiquitous classes of naturally occurring compounds, whereas the latter is the most xenobiotic and comprised virtually entirely of man‐made derivatives. Herein, 39 selected compounds, featuring both of these traits in the same molecule, are profiled. The total synthesis, source of the corresponding amino acids and fluorinated residues, and medicinal chemistry aspects and biological properties of the molecules are discussed.

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Hydantoin based inhibitors of MMP13—Discovery of AZD6605

Cited by 20 publications

References 26 publications

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

Isatin derivatives with activity against apoptosis-resistant cancer cells

Tailor‐Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals

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