Pyran-containing sulfonamide hydroxamic acids: potent MMP inhibitors that spare MMP-1

Reiter, Lawrence A.; Robinson, Ralph P.; McClure, Kim F.; Jones, Christopher S.; Reese, Matthew R.; Mitchell, Peter G.; Otterness, Ivan G.; Bliven, Marcia L.; Liras, Jennifer; Cortina, Santo R.; Donahue, Kathleen M.; Eskra, James D.; Griffiths, R.; Lame, Mary E.; Lopez‐Anaya, Arturo; Martinelli, Gary J.; McGahee, Shunda M.; Yocum, Sue A.; Lopresti‐Morrow, Lori; Tobiassen, Lisa M.; Vaughn-Bowser, Marcie L.

doi:10.1016/j.bmcl.2004.04.083

Cited by 57 publications

(19 citation statements)

References 33 publications

(15 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[56] Compound 3 was also identified to cause musculoskeletal syndrome (MSS), also known as tendinitis, in rats. [57] It was postulated that MMS was caused by the simultaneous inhibition of MMP-1 [58][59][60] and-14. [61,62] In 1995, Novartis disclosed the discovery of CGS-27023A (6; Figure 5);anon-peptidic stromelysin 1( MMP-3) inhibitor.…”

Section: Hydroxamate-based Zinc-binding Inhibitorsmentioning

confidence: 99%

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

Fischer

Senn

Riedl

2019

Chemistry A European J

View full text Add to dashboard Cite

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.

show abstract

Section: Hydroxamate-based Zinc-binding Inhibitorsmentioning

confidence: 99%

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

Fischer

Senn

Riedl

2019

Chemistry A European J

View full text Add to dashboard Cite

show abstract

“…13, 14 Yet the hydroxamic acid could present metabolic and pharmacokinetic challenges, including a short half-life and poor bioavailability. 1516, 17 The hydroxamate also chelates other biologically relevant metals, including Fe 2+ and Cu 2+ with affinities that can exceed that of Zn 2+ ion. 18, 19 Extensive reports have aimed to improve the HDAC inhibition profile by manipulating the surface recognition cap group and linker region while retaining the hydroxamic acid as ZBG.…”

Section: Introductionmentioning

confidence: 99%

3-Hydroxypyridin-2-thione as Novel Zinc Binding Group for Selective Histone Deacetylase Inhibition

et al. 2013

View full text Add to dashboard Cite

Small molecules bearing hydroxamic acid as the zinc binding group (ZBG) have been the most effective histone deacetylase inhibitor (HDACi) to date. However, concerns about the pharmacokinetic liabilities of the hydroxamic acid moiety have stimulated research efforts aimed at finding alternative non-hydroxamate ZBGs. We have identified 3-hydroxypyridin-2-thione (3-HPT) as a novel ZBG that is compatible with HDAC inhibition. 3-HPT inhibits HDAC 6 and HDAC 8 with an IC50 of 681 nM and 3675 nM respectively. Remarkably, 3-HPT gives no inhibition of HDAC 1. Subsequent optimization led to several novel 3HPT-based HDACi that are selective for HDAC 6 and HDAC 8. Furthermore, a subset of these inhibitors induces apoptosis in various cancer cell lines.

show abstract

“…Inhibitors of MMP-13, including RS 102481, and biphenylsulfonamide carboxylate,5 6 block the degradation of osteoarthritic cartilage, indicating the potential of MMP-13 as a promising target for osteoarthritis treatment drugs. However, the development of potential MMP-13 inhibitors has not progressed as expected, as a result of unanticipated side-effects7 and low oral bioavailability 6. Therefore, it is becoming increasingly important to focus research efforts on identifying the molecules and specific signalling pathways that regulate MMP-13 production in osteoarthritis chondrocytes.…”

mentioning

confidence: 99%