Synthesis and Structure−Activity Relationships of β- and α-Piperidine Sulfone Hydroxamic Acid Matrix Metalloproteinase Inhibitors with Oral Antitumor Efficacy

Becker, Daniel P.; Villamil, Clara I.; Barta, Thomas E.; Bedell, Louis J.; Boehm, Terri L.; DeCrescenzo, Gary; Freskos, John N.; Getman, Daniel P.; Hockerman, Susan L.; Heintz, R.; Howard, Susan C.; Li, Madeleine H.; McDonald, Joseph J.; Carron, Chris P.; Funckes-Shippy, Chris L.; Mehta, Pramod P.; Munie, Grace E.; Swearingen, Craig

doi:10.1021/jm0500875

Cited by 63 publications

(81 citation statements)

References 37 publications

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“…It has excellent oral efficacy in an animal model of osteoarthritis (equal to or superior to RS-130830) [80,81]. The thiophenoxyphenyl structure SC-276 has nearly identical sub-nanomolar K i values for MMP-2 and -13 inhibition as compared to its phenoxyphenyl cognate, and greatly improved MMP-1 sparing (SC-276 MMP-1 K i = 8700 nM, phenoxyphenyl cognate MMP-1 K i = 270 nM) [82]. SC-276 was orally active as an anti-angiogenic (mouse bFGF-stimulated corneal neovascularization) and as an anticancer (synergistic with paclitaxel in a mouse MX-1 carcinoma implant) [82].…”

Section: New Generation Hydroxamate-based Mmp Inhibitorsmentioning

confidence: 99%

Recent advances in MMP inhibitor design

Fisher

Mobashery

2006

Cancer Metastasis Rev

234

205

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The search for an MMP inhibitor with anticancer efficacy is a nearly three-decade endeavor. This inhibitor is yet to be found. The reasons for this failure include shortcomings in the chemistry of these compounds (including broad MMP sub-type selectivity, metabolic lability, and toxicity) as well as the emerging, and arguably extraordinary, complexity of MMP cell (and cancer) biology. Together these suggest that the successful anticancer inhibitor must possess MMP selectivity against the MMP subtype whose involvement is critical, yet highly temporally (with respect to metastatic progression) and mechanistically (with respect to matrix degradation) regulated. This review summarizes the progression of chemical structure and mechanistic thinking toward these objectives, with emphasis on the disappointment, the perseverance, and the resilient optimism that such an inhibitor is there to be discovered.

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Section: New Generation Hydroxamate-based Mmp Inhibitorsmentioning

confidence: 99%

Recent advances in MMP inhibitor design

Fisher

Mobashery

2006

Cancer Metastasis Rev

234

205

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“…It has been discovered that -sulfone hydroxamate inhibitors such as compounds B171-B183 [112] are superior to the -sulfone series represented by compounds B166-B170 [112] and B361 [6] in both enzyme profile and ADME properties. The affinity for MMP-1, MMP-2, MMP-3, MMP-8, MMP-9 and MMP-13 and the ADME properties of these compounds were studied by Becker et al [112]. They concluded that -sulfone hydroxamates have potency for the targeted MMPs but generally exhibit poor oral exposure.…”

Section: And Piperidine/tetrahydropyransulfonesmentioning

confidence: 99%

“…For the synthesis of -piperidine -sulfones [112], N-BOC protected ethyl piperidine-4-carboxylate was deprotonated with LDA and sulfinylated. After oxidation of the sulphide to sulfone, the deprotection of the amine, followed by N-alkylation, gave a variety of -sulfone esters which were transformed into hydroxamates using standard conditions.…”

Section: And Piperidine/tetrahydropyransulfonesmentioning

confidence: 99%

MMP-2 Selectivity in Hydroxamate-Type Inhibitors

Serra

Bruczko²,

Zapico³

et al. 2012

CMC

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Extracellular matrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases involved in physiological and pathological processes, through the cleavage of extracellular matrix. MMPs are capable of degrading essentially all matrix components, which is crucial for malignant tumor growth, invasion, metastasis and angiogenesis. The vertebrates MMP family includes at least 26 enzymes (23 have been known in humans) with only MMP-1, 2, and 7 experimentally validated as targets for antitumoral drug design. However, inhibition of MMP-1 has been hypothesized to be the cause of the clinically observed musculoskeletal syndrome when broad spectrum inhibitors are used. On the other hand, MMP-9 is a tricky enzyme, since its inhibition might be useful in treating patients with early-stage cancers, but MMP-9 is an anti-target in patients with advanced disease. So, MMP-9 inhibition should also be prevented. Therefore, selective MMP-2 inhibition arises as a pursued profile for MMP binders. Among them, hydroxamates have been extensively studied as small molecule drug candidates characterized by an effective zinc-binding group plus additional side chains responsible for the selectivity. This article pays particular attention to MMP-2 selectivity on hydroxamate-type inhibitors, especially against MMP-9, and their chemical structure, SAR, general synthetic methods, and molecular modelling studies are here reviewed in order to inspire further design of new effective anticancer agents.

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“…For example, MMP-1 and/or MMP-14 (MT1-MMP) inhibition was once considered to be the cause of clinical MSS and this led to the development of MMPIs (e.g. prinomastat) without inhibiting the enzymatic activity of MMP-1 and/or MMP-14, yet this hypothesis turned out to be unworkable in clinical trials [182,183]. 3) Inhibition of certain MMP(s) also affects other non-MMP proteases whose prime structure is similar with MMPs.…”

Section: Challenges Of Mmpi Researchmentioning

confidence: 99%

An Updated Patent Therapeutic Agents Targeting MMPs

Shi¹,

Shi³

et al. 2012

PRA

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The traditional consensus that matrix metalloproteinases (MMPs) has correlation with various pathological and physiological processes led to the exploitation of a vast number of natural or synthetic broad-spectrum MMP inhibitors (MMPIs) for the prophylaxis or treatment of various MMP-related disorders, such as autoimmune, inflammatory, cardiovascular, neurodegenerative, respiratory diseases, and malignant cancer as well. Yet the unsatisfactory preclinical and/or clinical results motivated further investigation of the physiological roles of certain MMP subtypes. Despite the intricate and complicated MMP functions in normal physiology and disease pathology, the effort of designing specific inhibitors that can selectively target certain MMP family members for individualized therapy is ongoing and remains an arduous task. Success will rely on continued insight into the biological roles of these multifaced proteases. In our previous effort, we summarized various MMPIs that have entered preclinical or clinical trials as well as the patents in regard to MMPIs (Recent Pat Anticancer Drug Discov. 2010; 5(2): 109-41). In our on-going review, to illustrate the major challenges in MMP validation as druggable targets, we highlighted the physiological and pathological roles of representative MMPs, with an emphasis on description of the newly emerging MMPI-based patents, in particular, the inhibitors containing sulfonamide or sulfone motif. By analyzing the structural characteristics and selectivity profiles of these supplementary inhibitors, we hereby described their pharmaceutical application, and also expanded the strategies for potent MMPI design.

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Synthesis and Structure−Activity Relationships of β- and α-Piperidine Sulfone Hydroxamic Acid Matrix Metalloproteinase Inhibitors with Oral Antitumor Efficacy

Cited by 63 publications

References 37 publications

Recent advances in MMP inhibitor design

Recent advances in MMP inhibitor design

MMP-2 Selectivity in Hydroxamate-Type Inhibitors

An Updated Patent Therapeutic Agents Targeting MMPs

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