Synthesis and Structure−Activity Relationship of N-Substituted 4-Arylsulfonylpiperidine-4-hydroxamic Acids as Novel, Orally Active Matrix Metalloproteinase Inhibitors for the Treatment of Osteoarthritis

Aranapakam, Venkatesan; Davis, Jamie M.; Grosu, G; Baker, Jannie; Ellingboe, John W.; Zask, Arie; Levin, Jeremy I.; Sandanayaka, Vincent; Du, Mila T.; Skotnicki, Jerauld S.; DiJoseph, John F.; Sung, Amy; Sharr, Michele A.; Killar, Loran M.; Walter, Thomas S.; Jin, Guixian; Cowling, Rebecca; Tillett, Jeff; Zhao, Weiguang; Mcdevitt, J. P.; Xu, Zhang Bao

doi:10.1021/jm0205550

Cited by 69 publications

(41 citation statements)

References 20 publications

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“…In a rabbit anterior cruciate ligament transection model, both MMP1 and -13 are known to be up-regulated (35). In a rabbit model in which anterior cruciate ligament transection was accompanied by removal of part of the meniscus (partial meniscectomy), a non-selective MMP inhibitor significantly reduced cartilage damage (36).…”

Section: Table 1 Contrasting the Mmp Selectivity Of Two Mmp13 Selectimentioning

confidence: 98%

Discovery and Characterization of a Novel Inhibitor of Matrix Metalloprotease-13 That Reduces Cartilage Damage in Vivo without Joint Fibroplasia Side Effects

Johnson¹,

Pavlovsky²,

Ortwine³

et al. 2007

Journal of Biological Chemistry

201

219

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Matrix metalloproteinase-13 (MMP13) is a Zn2؉ -dependent protease that catalyzes the cleavage of type II collagen, the main structural protein in articular cartilage. Excess MMP13 activity causes cartilage degradation in osteoarthritis, making this protease an attractive therapeutic target. However, clinically tested MMP inhibitors have been associated with a painful, joint-stiffening musculoskeletal side effect that may be due to their lack of selectivity. In our efforts to develop a disease-modifying osteoarthritis drug, we have discovered MMP13 inhibitors that differ greatly from previous MMP inhibitors; they do not bind to the catalytic zinc ion, they are noncompetitive with respect to substrate binding, and they show extreme selectivity for inhibiting MMP13. By structurebased drug design, we generated an orally active MMP13 inhibitor that effectively reduces cartilage damage in vivo and does not induce joint fibroplasias in a rat model of musculoskeletal syndrome side effects. Thus, highly selective inhibition of MMP13 in patients may overcome the major safety and efficacy challenges that have limited previously tested non-selective MMP inhibitors. MMP13 inhibitors such as the ones described here will help further define the role of this protease in arthritis and other diseases and may soon lead to drugs that safely halt cartilage damage in patients.The National Institutes of Health has estimated that more than 20 million adults in the United States suffer from osteoarthritis (OA), 3 a debilitating disease in which the protective cushion of cartilage is destroyed, resulting in pain and reduced mobility. A critical step in OA pathology is breakdown of the main structural protein of articular cartilage, type II collagen. This triple helical protein is resistant to most proteases but is efficiently recognized and degraded by the Zn 2ϩ -dependent enzyme, collagenase-3, known as matrix metalloproteinase-13 (MMP13) (1-3). MMP13 catalyzes the hydrolysis of type II collagen at a unique site resulting in 3 ⁄4-and 1 ⁄4-length polypeptide products (2-6). MMP13 is not found in normal adult tissues but is expressed in the joints and articular cartilage of OA patients (4 -8). In addition, regulated expression of human MMP13 in hyaline and joint cartilages induces OA in genetically modified mice (9). Furthermore, a MMP inhibitor that preferentially inhibits MMP13 has been shown to block the degradation of explanted human osteoarthritic cartilage (5). Based on these findings, it is likely that MMP13 is the direct cause of irreversible cartilage damage in OA.The clinical development of drugs that inhibit the actions of MMPs has been plagued by the association of a painful, joint-stiffening tendonitis-like side effect, termed "musculoskeletal syndrome" (MSS), with these inhibitors (10, 11). Such joint side effects are not unique to humans. Rats dosed with non-selective MMP inhibitors (i.e. compounds that inhibit several or all MMPs) also display MSS-like side effects such as soft tissue fibroplasias, inflammation, and pain (...

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Section: Table 1 Contrasting the Mmp Selectivity Of Two Mmp13 Selectimentioning

confidence: 98%

Discovery and Characterization of a Novel Inhibitor of Matrix Metalloprotease-13 That Reduces Cartilage Damage in Vivo without Joint Fibroplasia Side Effects

Johnson¹,

Pavlovsky²,

Ortwine³

et al. 2007

Journal of Biological Chemistry

201

219

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“…While both RS-130830 and 230954-09-3 are orally available, the shorter chain β-sulfonylhydroxamate class (exemplified by 239796-97-5 and SC-276) has improved ADME (especially metabolism) and MMP-1 selectivity properties. The phenoxyphenyl α-sulfonylpiperidinehydroxamate 239796-97-5 is an excellent MMP-9 and -13 inhibitor (IC 50 = 1 nM) that has a good TACE (IC 50 = 300 nM) sparing, and an excellent MMP-1 (IC 50 = 800 nM) sparing, profile [80,81]. It has excellent oral efficacy in an animal model of osteoarthritis (equal to or superior to RS-130830) [80,81].…”

Section: New Generation Hydroxamate-based Mmp Inhibitorsmentioning

confidence: 99%

“…The phenoxyphenyl α-sulfonylpiperidinehydroxamate 239796-97-5 is an excellent MMP-9 and -13 inhibitor (IC 50 = 1 nM) that has a good TACE (IC 50 = 300 nM) sparing, and an excellent MMP-1 (IC 50 = 800 nM) sparing, profile [80,81]. 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].…”

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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“…MMPs have long been considered excellent targets for treatment of osteoarthritis (OA), and inhibition of their activity has proven to be efficacious in a variety of models of experimentally induced as well as spontaneously occurring disease (2)(3)(4)(5). However, the clinical utility of broad-spectrum MMP inhibitors developed for treatment of OA has been restricted by dose-and duration-dependent musculoskeletal side effects in humans (joint stiffness, inflammation, pain in the hands, arms, and shoulders termed "musculoskeletal syndrome" [MSS]).…”

mentioning

confidence: 99%

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

Baragi

Becher²,

Bendele³

et al. 2009

Arthritis & Rheumatism

148

127

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Objective. Matrix metalloproteinases (MMPs) have long been considered excellent targets for osteoarthritis (OA) treatment. However, clinical utility of broad-spectrum MMP inhibitors developed for this purpose has been restricted by dose-limiting musculoskeletal side effects observed in humans. This study was undertaken to identify a new class of potent and selective MMP-13 inhibitors that would provide histologic and clinical efficacy without musculoskeletal toxicity.Methods. Selectivity assays were developed using catalytic domains of human MMPs. Freshly isolated bovine articular cartilage or human OA cartilage was used in in vitro cartilage degradation assays. The rat model of monoiodoacetate (MIA)-induced OA was implemented for assessing the effects of MMP-13 inhibitors on cartilage degradation and joint pain. The surgical medial meniscus tear model in rats was used to evaluate the chondroprotective ability of MMP-13 inhibitors in a chronic disease model of OA. The rat model of musculoskeletal side effects (MSS) was used to assess whether selective MMP-13 inhibitors have the joint toxicity associated with broad-spectrum MMP inhibitors.Results. A number of non-hydroxamic acidcontaining compounds that showed a high degree of potency for MMP-13 and selectivity against other MMPs were designed and synthesized. Steady-state kinetics experiments and Lineweaver-Burk plot analysis of rate versus substrate concentration with one such compound, ALS 1-0635, indicated linear, noncompeti-

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Synthesis and Structure−Activity Relationship of N-Substituted 4-Arylsulfonylpiperidine-4-hydroxamic Acids as Novel, Orally Active Matrix Metalloproteinase Inhibitors for the Treatment of Osteoarthritis

Cited by 69 publications

References 20 publications

Discovery and Characterization of a Novel Inhibitor of Matrix Metalloprotease-13 That Reduces Cartilage Damage in Vivo without Joint Fibroplasia Side Effects

Discovery and Characterization of a Novel Inhibitor of Matrix Metalloprotease-13 That Reduces Cartilage Damage in Vivo without Joint Fibroplasia Side Effects

Recent advances in MMP inhibitor design

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

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