Design and Synthesis of Phosphinamide-Based Hydroxamic Acids as Inhibitors of Matrix Metalloproteinases

Pikul, S.; Dunham, Kelly L. McDow; Almstead, Neil G.; De, Biswanath; Natchus, Michael G.; Anastasio, M.V; McPhail, Sara J.; Snider, Catherine E.; Taiwo, Yetunde O.; Chen, Longyin; Dunaway, C. M.; Gu, and Fei; Mieling, Glen E.

doi:10.1021/jm980142s

Cited by 78 publications

(49 citation statements)

References 14 publications

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“…A major limitation for clinical use of this group is the hydrolysis of the phosphinamide bond in acidic conditions, leading to their inadequate bioavailability orally [115,132].…”

Section: Mmp Inhibitors and Potential Benefits In Varicose Veinsmentioning

confidence: 99%

Matrix Metalloproteinases in Venous Tissue Remodeling and Varicose Vein Formation

Raffetto¹,

Khalil²

2008

CVP

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Matrix metalloproteinases (MMPs) play a major role in extracellular matrix (ECM) turnover under both physiological and pathological conditions. Studies on venous tissues from experimental animals and humans identified several MMP subtypes, and showed significant changes in the expression and activity of specific MMPs during vein wall remodeling. Also, significant research has focused on the role of MMPs in chronic venous disease (CVD) and varicose vein formation in the lower extremities and their progression to thrombophlebitis and venous leg ulcer. Several hypotheses have been forwarded regarding the pathophysiological mechanisms underlying the relation between MMPs and the formation, progression and complications of varicose veins. The effects of MMPs on ECM degradation could result in significant venous tissue remodeling and degenerative and structural changes in the vein wall, leading to venous dilation and valve dysfunction. MMPs may also induce early changes in the endothelium and venous smooth muscle function in the absence of significant ECM degradation or structural changes in the vein wall. In addition, evidence suggests increased activity of MMPs in the advanced stages of chronic venous insufficiency (CVI) associated with skin changes and leg ulceration as well as in the wound fluid environment. Several pharmacological therapies and surgical strategies are being utilized in the management of varicose veins, with variable success and recurrence rates. Inhibition of MMPs may represent a novel therapeutic intervention to limit the progression of varicose veins to CVI and leg ulceration.

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“…A major limitation for clinical use of this group is the hydrolysis of the phosphinamide bond in acidic conditions, leading to their inadequate bioavailability orally [115,132].…”

Section: Mmp Inhibitors and Potential Benefits In Varicose Veinsmentioning

confidence: 99%

Matrix Metalloproteinases in Venous Tissue Remodeling and Varicose Vein Formation

Raffetto¹,

Khalil²

2008

CVP

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“…9 The MMP inhibitor chosen for this study was PGE7113313 (Procter and Gamble), which based on initial in vitro assay systems, exhibited a 50% inhibitory concentration (IC 50 ) for MMP-2 of 1.5 nmol/L, MMP-3 of 13 nmol/L, MMP-8 of 1.9 nmol/L, MMP-9 of 1 nmol/L, and MMP-13 of 1.1 nmol/L. 15 However, the IC 50 of this compound for MMP-1 was greater than 4000 nmol/L. This MMP inhibitor did not influence TNF-␣ release in a THP-1 cell culture assay, nor affected angiotensin-converting enzyme activity based on an enzymatic assay.…”

Section: Selective Mmp Inhibitionmentioning

confidence: 99%

Selective Matrix Metalloproteinase Inhibition With Developing Heart Failure

King

Coker

Goldberg

et al. 2003

Circulation Research

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Abstract-The matrix metalloproteinases (MMPs) are an endogenous family of proteolytic enzymes implicated to contribute to LV remodeling. However, broad-spectrum MMP inhibition (MMPi), particularly inhibition of interstitial collagenase (MMP-1), may not be clinically applicable. This study examined the effects of selective MMPi (sparing MMP-1) in a model of developing congestive heart failure. Pigs were randomly assigned to 3 groups: (1) rapid pacing for 3 weeks (240 bpm, nϭ10); (2) selective MMPi (20 mg/kg per day-PO;PGE7113313) and rapid pacing (nϭ12); and (3) controls (nϭ10 Key Words: left ventricular systolic function Ⅲ myocardial stiffness Ⅲ myocardial structure Ⅲ matrix metalloproteinases Ⅲ heart failure A structural milestone in the progression of congestive heart failure (CHF) is alterations in left ventricular (LV) geometry, commonly referred to as myocardial remodeling. The myocardial extracellular matrix contributes to the maintenance of LV geometry, structural alignment of adjoining myocytes, as well as modulating transmembrane signaling pathways. A family of enzymes that contributes to extracellular collagen degradation and tissue remodeling is the matrix metalloproteinases (MMPs). 1-3 Increased expression and activity of MMPs within the LV myocardium occurs in both patients and animals with CHF. 4 -8 Orally active nonselective MMP inhibitors, termed as broad spectrum MMP inhibitors, have been used in several animal models of CHF and demonstrated to attenuate the LV remodeling process. 7-9 Therefore, modulating MMP activity represents a potential therapeutic target in the context of LV remodeling and CHF. However, long-term inhibition of all MMP species will likely interfere with normal tissue remodeling processes and can give rise to undesirable systemic effects. 10 -12 Thus, selective targeting of MMP species that contribute to pathological myocardial remodeling in developing CHF will likely hold greater therapeutic potential. Whereas a number of MMP species are expressed within the human myocardium, not all MMPs are upregulated in end-stage CHF. 6,13,14 Specifically, the abundance of interstitial collagenase-1, or MMP-1, is significantly reduced in patients with cardiomyopathic disease. 6 However, it remains unknown whether inhibition of MMP-1 is a fundamental requirement in order to alter the myocardial remodeling process during the initiation and development of CHF. Accordingly, the overall goal of this study was to institute selective MMP inhibition that would effectively spare MMP-1 inhibition in an animal model of developing CHF. Materials and Methods Selective MMP InhibitionPast studies have demonstrated that several classes of MMPs are increased in CHF including the interstitial collagenase MMP-13, stromelysins such as MMP-3, and the gelatinases such as MMP-2 and MMP-9. 4 -8,14 In order to identify an MMP inhibition dosage regimen that would provide acceptable plasma profiles with respect to inhibition of these species but effectively spare MMP-1 inhibition, pharmacokinetic studies were p...

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“…A new series of hydroxamic acid-based MMP inhibitors containing a phosphinamide motif derived from D-amino acids has been reported [209]. Compounds with an (R)-configuration at phosphorous were found to be potent MMP inhibitors, while molecules with the (S)-configuration were inactive.…”

Section: Phosphorous-based Inhibitors and Miscellaneous Inhibitors Ofmentioning

confidence: 99%

The Design, Structure, and Therapeutic Application of Matrix Metalloproteinase Inhibitors

Skiles¹,

Gonnella²,

Jeng³

2001

CMC

211

144

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Matrix metalloproteinases (MMPs) are a family of zinc-containing enzymes involved in the degradation and remodeling of extracellular matrix proteins. The activities of these enzymes are well regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Chronic stimulation of MMP activities due to an imbalance in the levels of MMPs and TIMPs has been implicated in the pathogenesis of a variety of diseases such as cancer, osteoarthritis, and rheumatoid arthritis. Thus, MMP inhibitors are expected to be useful for the treatment of these disorders. This article reviews briefly the biochemistry of MMPs and evidence for their pathogenic roles using molecular biology approaches. Biomolecular structures used in the design of MMP inhibitors are thoroughly covered. Major emphasis is on recently published potent, small molecular weight MMP inhibitors and their pharmacological properties. Finally, available clinical results of compounds in development are summarized.

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Design and Synthesis of Phosphinamide-Based Hydroxamic Acids as Inhibitors of Matrix Metalloproteinases

Cited by 78 publications

References 14 publications

Matrix Metalloproteinases in Venous Tissue Remodeling and Varicose Vein Formation

Matrix Metalloproteinases in Venous Tissue Remodeling and Varicose Vein Formation

Selective Matrix Metalloproteinase Inhibition With Developing Heart Failure

The Design, Structure, and Therapeutic Application of Matrix Metalloproteinase Inhibitors

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