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MMP Inhibitors (mmp + inhibitor)
Kinds of MMP Inhibitors Selected AbstractsSynthesis and SAR of Diazepine and Thiazepine TACE and MMP Inhibitors.CHEMINFORM, Issue 29 2005Arie Zask Abstract For Abstract see ChemInform Abstract in Full Text. [source] Pyran-Containing Sulfonamide Hydroxamic Acids: Potent MMP Inhibitors that Spare MMP-1.CHEMINFORM, Issue 41 2004Lawrence A. Reiter Abstract For Abstract see ChemInform Abstract in Full Text. [source] ChemInform Abstract: The Discovery of Anthranilic Acid-Based MMP Inhibitors.CHEMINFORM, Issue 15 2001Part 1. Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Synthetic matrix metalloproteinase inhibitor decreases early cardiac neural crest migration in chicken embryosDEVELOPMENTAL DYNAMICS, Issue 4 2002D.H. Cai Abstract During early embryonic development, cardiac neural crest (NC) cells emerge from the forming neural tube, migrate beneath the ectoderm, enter the pharyngeal arches, and subsequently participate in the septation of the heart. Like tumor cells, NC cells penetrate through basement membranes and invade extracellular matrix during their emigration and migration and, therefore, are liable to use similar invasive mechanisms. Matrix metalloproteinases (MMPs) are a family of zinc proteolytic enzymes known to be important in cell migration and invasion of normal and metastatic cells. In an earlier study, we found that the spatial and temporal distribution pattern of MMP-2 positively correlates with cardiac NC migration, suggesting MMP enzymatic activity may be important in mediating cardiac cell NC migration. To test this hypothesis, a synthetic MMP inhibitor, KB8301, was used to block MMP enzymatic activity during in vitro and in vivo cardiac NC cell migration in chick embryos. Injection of KB8301 into the cell-free space adjacent to the neural tube at the level of the second somite before the NC cells emigrated caused major morphologic anomalies in embryos and disrupted cardiac NC morphogenesis. Unilateral injection of KB8301 at lower concentrations, significantly decreased cardiac NC migration on the injected side compared with the noninjected side and compared with that of the injected controls. This decrease correlated with a decrease in MMP activity in the embryos and was not attributable to differences in embryo size or rate of embryonic development after injection. KB8301 also significantly decreased the rate of NC cell motility and distance NC cells migrated from explanted neural tubes and increased cell area and perimeter. These data suggest that MMP enzymatic activity is an important mediator of early cardiac NC migration and that perturbation of endogenous MMP activity may lead to NC-related congenital defects. © 2002 Wiley-Liss, Inc. [source] Matrix metalloproteinase inhibitor, CTS-1027, attenuates liver injury and fibrosis in the bile duct-ligated mouseHEPATOLOGY RESEARCH, Issue 8 2009Alisan Kahraman Aim:, Excessive matrix metalloproteinase (MMP) activity has been implicated in the pathogenesis of acute and chronic liver injury. CTS-1027 is an MMP inhibitor, which has previously been studied in humans as an anti-arthritic agent. Thus, our aim was to assess if CTS-1027 is hepato-protective and anti-fibrogenic during cholestatic liver injury. Methods:, C57/BL6 mice were subjected to bile duct ligation (BDL) for 14 days. Either CTS-1027 or vehicle was administered by gavage. Results:, BDL mice treated with CTS-1027 demonstrated a threefold reduction in hepatocyte apoptosis as assessed by the TUNEL assay or immunohistochemistry for caspase 3/7-positive cells as compared to vehicle-treated BDL animals (P < 0.01). A 70% reduction in bile infarcts, a histological indicator of liver injury, was also observed in CTS-1027-treated BDL animals. These differences could not be ascribed to differences in cholestasis as serum total bilirubin concentrations were nearly identical in the BDL groups of animals. Markers for stellate cell activation (,-smooth muscle actin) and hepatic fibrogenesis (collagen 1) were reduced in CTS-1027 versus vehicle-treated BDL animals (P < 0.05). Overall animal survival following 14 days of BDL was also improved in the group receiving the active drug (P < 0.05). Conclusion:, The BDL mouse, liver injury and hepatic fibrosis are attenuated by treatment with the MMP inhibitor CTS-1027. This drug warrants further evaluation as an anti-fibrogenic drug in hepatic injury. [source] Induction of colonic transmural inflammation by bacteroides fragilis.INFLAMMATORY BOWEL DISEASES, Issue 2 2005Implication of Matrix Metalloproteinases Abstract Background: Commensal bacteria are implicated in the pathophysiology of intestinal inflammation, but the precise pathogenetic mechanisms are not known. We hypothesized that Bacteroides fragilis -produced metalloproteinases (MMPs) are responsible for bacterial migration through the intestinal wall and transmural inflammation. Aim: To investigate the role of bacterial-MMP activity in an experimental model of colitis induced by the intramural injection of bacteria. Methods: Suspensions of viable B. fragilis or Escherichia coli were injected into the colonic wall, and the effect of the MMP inhibitor (phenantroline) on histologic lesion scores was tested. MMP activity in bacterial suspensions was measured by azocoll assay. Results: The inoculation with B. fragilis induced chronic inflammatory lesions that were preferentially located in the subserosa, whereas inoculation with E. coli induced acute-type inflammatory reactions, evenly distributed in both the submucosa and subserosa. Treatment with phenantroline significantly decreased subserosal lesion scores in rats inoculated with B. fragilis, but not in rats inoculated with E. coli. Bacterial suspensions of B. fragilis showed MMP activity, but E. coli suspensions did not. Sonication of B. fragilis reduced MMP activity and virulence to induce serosal lesions. Conclusion: Our data suggest that bacterial MMPs may be implicated in the serosal migration of B. fragilis and in the induction of transmural inflammation. [source] Upregulation of MMP-9/TIMP-1 enzymatic system in eosinophilic meningitis caused by Angiostrongylus cantonensisINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 2 2005Ke-Min Chen Summary Proteolysis depends on the balance between the proteases and their inhibitors. Matrix metalloproteinase-9 (MMP-9) and its specific inhibitors, tissue inhibitors of metalloproteinases (TIMP), contribute to eosinophilic inflammatory reaction in the subarachnoid space of the Angiostrongylus cantonensis -infected mice. The expression of MMP-9 in cerebrospinal fluid (CSF) was significantly increased in mice with eosinophilic meningitis, compared to that in uninfected ones. However, the TIMP-1 levels were unchanged and remained at basal levels at all time points, even in uninfected mice. Elevated MMP-9 mRNA expression coincided with protein levels and proteolytic activity, as demonstrated by means of positive immunoreactivity and gelatin zymography. CSF protein contents correlated significantly with MMP-9 intensity and CSF eosinophilia. In addition, immunohistochemistry demonstrated MMP-9 and TIMP-1 localization in eosinophils and macrophages. When the specific MMP inhibitor, GM6001, was added, MMP-9 enzyme activity was reduced by 45.4%. The percentage of eosinophil increased significantly upon the establishment of infection, but subsided upon inhibition. These results show that MMP-9/TIMP-1 imbalance in angiostrongyliasis may be associated with eosinophilic meningitis. [source] Inhibition of Obliterative Airway Disease Development in Murine Tracheal Allografts by Matrix Metalloproteinase-9 DeficiencyAMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2005Félix G. Fernández This study was designed to define the roles of matrix metalloproteinase (MMP)-2 and MMP-9 in obliterative airway disease (OAD) in heterotopic murine tracheal allografts, considered a suitable animal model for chronic lung allograft rejection. BALB/c tracheal allografts were transplanted into MMP-2-deficient (,/,) and MMP-9,/, mice. Also, wild-type recipients were treated with doxycycline, a nonspecific MMP inhibitor. After 10, 20 and 30 days, allografts were analyzed for OAD development, intragraft levels of MMP-2 and MMP-9 and the frequency and cytokine/chemokine production profile of alloreactive T cells. Allografts transplanted into wild-type mice developed OAD lesions within 30 days. These allografts revealed significant upregulation of both MMP-2 and MMP-9. Allografts transplanted into MMP-9,/, and doxycycline-treated recipients did not develop OAD. In contrast, allografts transplanted into MMP-2,/, mice developed OAD lesions with normal kinetics. Interestingly, MMP-9,/, recipients showed an enhanced T cell alloreactivity associated with an abnormal profile of cytokine/chemokine production. The enhanced T cell alloreactivity in MMP-9,/, mice was mediated by enhanced dendritic cell stimulatory capacity as well as enhanced T cell responsive capacity. These results suggest that MMP-9 plays an important role in the pathogenesis of OAD and may represent a target for the therapeutic intervention of chronic lung allograft rejection. [source] In vitro model for penetration of sensory nerve fibres on a Matrigel basement membrane: implications for possible application to intractable pruritusBRITISH JOURNAL OF DERMATOLOGY, Issue 5 2009M. Tominaga Summary Background, Epidermal hyperinnervation occurs in dermatoses with intractable pruritus, such as atopic dermatitis, suggesting that the hyperinnervation is partly responsible for abnormal itch perception. Objectives, To investigate the mechanisms of penetration of sensory nerve fibres into the basement membrane of the skin. Methods, A rat dorsal root ganglion neurone culture system consisting of Matrigel and a Boyden chamber containing a nerve growth factor (NGF) concentration gradient was used. In some experiments, matrix metalloproteinase (MMP) blockers and semaphorin 3A (Sema3A) were added to the culture system. Matrigel-coated membranes were stained with anti-Tau antibody, and the number of nerve fibres that crossed the membrane was counted. Expression of MMPs in the cultured neurones was examined at mRNA and protein levels by quantitative reverse transcription,polymerase chain reaction and immunocytochemistry, respectively. The activity was also examined by zymography. Results, Nerve fibres penetrated into Matrigel in the presence of an NGF concentration gradient, which was dose-dependently inhibited by GM6001, a broad-spectrum MMP inhibitor. Transcripts for MMP2, but not MMP9, were increased in the cultured neurones, and the penetration was dose-dependently inhibited by MMP-2 blockers. MMP-2 and its activity were partially localized on the NGF-responsive growth cones. NGF also upregulated pro-MMP-2 activation molecules in the cultured neurones. Sema3A stimulation showed the opposite effects on these NGF-dependent events. Interestingly, MMP2 expression was modulated by extracellular matrix (ECM) substrates for this enzyme. Conclusions, Membrane-associated MMP-2 contributes to penetration of nerve fibres into Matrigel through modulation by axonal guidance molecules and/or ECM. These findings provide insight for understanding the development of intractable pruritus involving epidermal nerve density. [source] Keloid-derived fibroblasts show increased secretion of factors involved in collagen turnover and depend on matrix metalloproteinase for migrationBRITISH JOURNAL OF DERMATOLOGY, Issue 2 2005M. Fujiwara Summary Background, ,A keloid is a specific skin lesion that expands beyond the boundaries of the original injury as it heals. Histologically, it is characterized by the excessive accumulation of collagen. However, the reasons for the expansion and the invasive nature of keloids remain unknown. Objectives, We evaluated collagen degradation and migration by cultured keloid fibroblasts based on the assumption that these variables were of functional relevance to the expanding and invasive nature of keloid lesions. Methods, Collagen production was investigated by the detection of type 1 collagen (procollagen type 1C peptide: P1P). Matrix metalloproteinase (MMP)-1 (interstitial collagenase) and MMP-2 (gelatinase-A), were investigated as elements of the collagen degradation system. Enzyme immunoassays were performed to measure the production of P1P, MMP-1, MMP-2, and tissue inhibitor of metalloproteinase (TIMP)-1. To assess the production of MMP-2 its gelatinolytic activity was measured by zymography using gelatin-containing gels. The participation of transforming growth factor-,1 (TGF-,1) in the production and degradation of collagen was also investigated. Finally, the migratory activity of keloid fibroblasts was evaluated using a colony dispersion assay. Results, The production of type 1 collagen, MMP-1, MMP-2, and TIMP-1 by keloid fibroblasts was 3-fold, 6-fold, 2·4-fold, and 2-fold greater than that of normal dermal fibroblasts, respectively. Production of P1P was increased when TGF-,1 was added to cultures of keloid fibroblasts, while it was decreased when anti-TGF-,1 antibody was added to the cultures. In contrast, the production of MMP-1 was decreased by the addition of TGF-,1 to cultured keloid fibroblasts, while it was increased when anti-TGF-,1 antibody was added to the cultures. The production of MMP-2 increased after treatment with TGF-,1, but did not change significantly when anti-TGF-,1 antibody was added to the cultures. Production of TIMP-1 did not change significantly when either TGF-,1 or anti-TGF-,1 antibody was added to the cultures. Keloid fibroblasts showed a 2·5-fold increase of migratory activity compared with normal dermal fibroblasts, while the migratory activity of these fibroblasts was reduced to the control level by treatment with a broad-spectrum MMP inhibitor (GM 6001). Conclusions, Cultured keloid fibroblasts showed increased production of collagen and MMPs, and TGF-,1 played a role in this regulation of production. In addition, increased production of MMPs had a role in the high migratory activity of cultured keloid fibroblasts. [source] Phase 1/2 trial of BMS-275291 in patients with human immunodeficiency virus-related Kaposi sarcoma,,CANCER, Issue 5 2008A multicenter trial of the AIDS Malignancy Consortium Abstract BACKGROUND. Matrix metalloproteinases (MMPs) are overexpressed in Kaposi sarcoma (KS). The safety and efficacy of a novel, orally bioavailable MMP inhibitor, BMS-275291, was evaluated in patients with human immunodeficiency virus-associated KS and the correlation between changes in the percentage of apoptotic cells in tumor biopsies and response was explored. METHODS. Cohorts of 6 patients were to be treated with BMS-275291. The initial cohort received 1200 mg once a day; subsequent doses were to be escalated to 600 mg twice daily and 1200 mg twice daily, or decreased to 600 mg/day. Tumor biopsies for apoptosis assays were collected pretreatment and on Day 29. Prospectively defined dose level adjustments were to be based on dose-limiting toxicity (DLT), tolerability, changes in the percentage of apoptotic cells, and treatment response. RESULTS. Sixteen patients were enrolled; 15 received the study drug and could be evaluated. The median duration of treatment was 20 weeks (range, 3,54 weeks). A dose of 1200 mg once a day was well tolerated but induced only 1 response. A DLT occurred in 3 patients treated with 600 mg twice daily, and included grade 3 fatigue, grade 3 allergic reaction, and grade 3 arthralgias; 2 responses were noted at this dose level (toxicity was graded according to the National Cancer Institute Common Toxicity Criteria [version 2.0]). Based on predetermined endpoints, the trial was closed after accrual of 15 treated patients. Assessment of biologic response for dose escalation/de-escalation decisions utilizing the apoptosis assay was not feasible. CONCLUSIONS. BMS-275291 given at a dose of 600 mg twice daily induced unacceptable toxicity. The better-tolerated schedule of 1200 mg once a day demonstrated inadequate efficacy in patients with human immunodeficiency virus-associated KS. The apoptosis assay was not helpful in predicting response. Cancer 2008. © 2008 American Cancer Society. [source] Synthesis of a Cyclic Analogue of GalardinCHINESE JOURNAL OF CHEMISTRY, Issue 3 2001Da-Wei Ma Abstract A cyclic analogue 4 of galardin, a known MMP inhibitor, is designed to improve its selectivity. The synthesis of 4 starts from dimethyl (S)-malate using diaselective alkylation and subsequent cyclization and amide formation as key steps. The compound 4 showed MMP inhibitory activity on all MMPs tested with IC30, ranging from 20.1 ,M to 104 ,M. [source] Subventricular zone-derived neuroblast migration to the olfactory bulb is modulated by matrix remodellingEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2007Serena Bovetti Abstract In the rodent brain neural progenitor cells are born in the subventricular zone and migrate along a pathway called the rostral migratory stream (RMS) into the olfactory bulb where they differentiate into several classes of interneurones. In the adult, tangential migration in the RMS takes place in ,chains' of cells contained within glial tubes. In contrast, neonatal neuroblasts along the RMS lack these defined glial tubes and chains, migrating instead as individual cells. Time-lapse confocal microscopy of neuroblasts at each of these ages shows that individual cells migrate in a saltatory manner with bursts of high speed followed by periods of slower speed. Tangential migration within a glial tube is 20% faster than migration as individual cells. Neuroblasts may also interact and modify the extracellular matrix during migration through expression of a family of proteins, the matrix metalloproteinases (MMPs). MMPs are present and active along the subventricular zone,olfactory bulb pathway. In the presence of inhibitors of MMPs, neuroblast migration rates were reduced only when cells migrate individually. Chain migration in the adult was unaffected by MMP inhibitors. Taken together, these data suggest that MMPs only influence migration as individual cells and not as chains. [source] Distinct progression-associated expression of tumor and stromal MMPs in HaCaT skin SCCs correlates with onset of invasionINTERNATIONAL JOURNAL OF CANCER, Issue 10 2009Silvia Vosseler Abstract Matrix metalloproteinases (MMPs) are critically involved in tumor invasion and metastasis. However, failure of broad spectrum MMP inhibitors in clinical trials emphasizes the need for detailed analyses of the specific role of different MMPs in tumor malignancy. Using HaCaT-keratinocyte clones representing distinct stages in skin squamous cell carcinoma (SCC) progression, we demonstrate the expression of specific tumor and stroma-derived MMPs with the onset and maintenance of tumor invasion. Although MMP-9-positive leukocytes are present in benign and malignant tumor transplants at the onset of stromal activation and angiogenesis, mRNA expression of stroma-derived MMP-9 as well as MMP-2, ,13 and ,14 is exclusively found in enhanced malignant tumor transplants. Their expression initiates with the onset of invasion, whereas being absent in early noninvasive stages of malignant transplants. In addition, a high expression of tumor-derived MMP-1, ,2 and ,14 contributes to malignant and invasive tumor growth. However, stroma-derived MMP-3 is exclusively restricted to very late-stage invasive and malignant transplants. The functional contribution of these proteases to invasive growth is supported by the gelatinolytic activity in the tumor transplants that again initiates with the onset of invasive growth suggesting a crucial role of MMP-2, ,9, ,13 and ,14 for the establishment of a reactive stroma that promotes tumor invasion. These data demonstrate a complex cooperation of distinct tumor and stroma-derived MMPs in the establishment of malignant tumors and provide the basis for a more specific use of highly selective MMP inhibitors during distinct stages of tumor progression. © 2009 UICC [source] Increased plasma MMP9 in integrin ,1-null mice enhances lung metastasis of colon carcinoma cellsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2005Xiwu Chen Abstract Inhibitors of matrix metalloproteinases (MMPs) were developed as anticancer agents based on the observation that MMPs facilitate local tumor spread and metastasis by promoting matrix degradation and cell migration. Unfortunately, these inhibitors were unsuccessful in the clinical treatment of several cancers, including lung cancer. A possible reason contributing to their failure is that MMP activity is critical for the generation of inhibitors of tumor angiogenesis, including angiostatin. Thus, MMPs might play opposing roles in tumor vascularization and invasion. To determine which effect of elevated MMP levels dominates in the progression of metastatic cancer, experimental lung metastasis assays were performed in integrin ,1-null mice, a genetic model for increased plasma levels of MMP9 and MMP9-generated angiostatin (Pozzi et al., Proc. Natl. Acad. Sci. USA 2000;97:2202,7). We show that while the number of lung colonies in integrin ,1-null mice was significantly increased compared to their wild-type counterparts, tumor volume was markedly reduced. In vivo treatment with the MMP inhibitor doxycycline resulted in a significant decrease in the number of lung colonies in both genotypes, but the tumors that formed were bigger and more vascularized. Increased tumor vascularization paralleled decreased plasma levels of MMP9 and consequent decreased angiostatin synthesis. These results demonstrate that while inhibition of MMPs prevents and/or reduces tumor invasion and lung metastasis, it has the paradoxical effect of increasing the size and vascularization of metastatic tumors due to decreased generation of inhibitors of endothelial cell proliferation. The continued growth of these large well-vascularized tumors may explain the poor efficacy of MMP inhibitors in lung cancer clinical trials. © 2005 Wiley-Liss, Inc. [source] Matrix metalloproteinase 11 (MMP-11; stromelysin-3) and synthetic inhibitorsMEDICINAL RESEARCH REVIEWS, Issue 4 2007Magdalini Matziari Abstract Matrix metalloproteinase (MMP)-11, or Stromelysin 3, is a particular member of MMP family, a group of zinc-dependent endopeptidases involved in matrix degradation and tissue remodeling. Despite intense efforts since its first characterization 15 years ago, its role and target substrates in different diseases remain largely unknown. While mice with MMP-11 deficiency display no particular phenotype, analysis of different tumorigenesis models with these mice lead to the conclusion that MMP-11 promotes tumor development. In contrast with other MMPs, MMP-11 is unable to degrade any major extracellular matrix component and unlike most of other MMPs that are secreted as inactive proenzymes and activated extracellularly, MMP-11 is secreted under active form. MMP-11 may thus play a unique role in tissue remodeling processes, including those associated with tumor progression. Although MMP-11 and other MMPs have been considered as promising targets to combat cancer, a first series of clinical trials using broad-spectrum MMP inhibitors have not led to significant therapeutic benefits. These disappointing results highlight the need for better understanding of the exact role played by each MMP during the different stages of tumor progression. Among the different strategies to fill this gap, highly specific MMP inhibitors would be of great value. This review provides an update on the selectivity profile of phosphinic MMP-11 synthetic inhibitors developed and discusses the opportunities and limitations to identify inhibitors able to fully discriminate MMP-11 from the other MMPs. © 2006 Wiley Periodicals, Inc. Med Res Rev, 27, No. 4, 528,552, 2007 [source] Characterization of an exosite binding inhibitor of matrix metalloproteinase 13PROTEIN SCIENCE, Issue 1 2008Lata T. Gooljarsingh Abstract Matrix metalloproteinase 13 (MMP13) is a key enzyme implicated in the degradation of the extracellular matrix in osteoarthritis. Clinical administration of broad spectrum MMP inhibitors such as marimastat has been implicated in severe musculo-skeletal side effects. Consequently, research has been focused on designing inhibitors that selectively inhibit MMP13, thereby circumventing musculo-skeletal toxicities. A series of pyrimidine dicarboxamides were recently shown to be highly selective inhibitors of MMP13 with a novel binding mode. We have applied a molecular ruler to this exosite by dual inhibition studies involving a potent dicarboxamide in the presence of two metal chelators of different sizes. A larger hydroxamate mimic overlaps and antagonizes binding of the dicarboxamide to the exosite whereas the much smaller acetohydroxamate synergizes with the dicarboxamide. These studies elucidate the steric requirement for compounds that fit exclusively into the active site, a mandate for generating highly selective MMP13 inhibitors. [source] MMP-Dependent Migration of Extrapulmonary Myofibroblast Progenitors Contributing to Posttransplant Airway Fibrosis in the LungAMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2009M. Sato Myofibroblasts play a central role in fibroproliferative airway remodeling in obliterative bronchiolitis (OB) after lung transplantation. The purpose of the study is to elucidate the mechanisms whereby matrix metalloproteinases (MMPs) contribute to myofibroblast-mediated allograft airway fibrosis. In an intrapulmonary tracheal transplant model of OB, broad-spectrum MMP inhibitors, SC080 and MMI270 reduced the number of myofibroblasts at day 28 without changing differentiation, proliferation or apoptosis of myofibroblasts or fibroblasts. Next, myofibroblasts in allograft airway fibrosis were demonstrated to be almost exclusively of extrapulmonary origin by analyzing RT1An positive myofibroblasts in an animal model combining orthotopic lung transplantation (from Lewis (RT1Al) to F1 (Brown,Norway (RT1An) × Lewis)) and intrapulmonary tracheal transplantation (from a Wister,Furth rat (RT1Au) into the transplanted Lewis-derived lung). Using peripheral blood mononuclear cells (PBMCs) that can differentiate into ,-SMA positive myofibroblasts in vitro, we demonstrated their contribution to the myofibroblast population of allograft airway fibrosis in vivo using a fluorescence-labeling cell tracking system. Moreover, PBMC-derived fibroblast-like cells expressed high levels of MMP-9 and MMP-12 and their migration was inhibited by MMP inhibitors in a wound healing assay. In conclusion, MMP-dependent migration of PBMC-derived myofibroblast precursors is an important contributing mechanism to the development of allograft airway fibrosis. [source] 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 modelsARTHRITIS & RHEUMATISM, Issue 7 2009Vijaykumar M. Baragi 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 acid,containing 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, noncompetitive inhibition, and Dixon plot analysis from competition studies with a zinc chelator (acetoxyhydroxamic acid) and ALS 1-0635 demonstrated nonexclusive binding. ALS 1-0635 inhibited bovine articular cartilage degradation in a dose-dependent manner (48.7% and 87.1% at 500 nM and 5,000 nM, respectively) and was effective in inhibiting interleukin-1,, and oncostatin M,induced C1,C2 release in human OA cartilage cultures. ALS 1-0635 modulated cartilage damage in the rat MIA model (mean ± SEM damage score 1.3 ± 0.3, versus 2.2 ± 0.4 in vehicle-treated animals). Most significantly, when treated twice daily with oral ALS 1-0635, rats with surgically induced medial meniscus tear exhibited histologic evidence of chondroprotection and reduced cartilage degeneration, without observable musculoskeletal toxicity. Conclusion The compounds investigated in this study represent a novel class of MMP-13 inhibitors. They are mechanistically distinct from previously reported broad-spectrum MMP inhibitors and do not exhibit the problems previously associated with these inhibitors, including selectivity, poor pharmacokinetics, and MSS liability. MMP-13 inhibitors exert chondroprotective effects and can potentially modulate joint pain, and are, therefore, uniquely suited as potential disease-modifying osteoarthritis drugs. [source] A Macrophage Cell Model for Selective Metalloproteinase Inhibitor DesignCHEMBIOCHEM, Issue 13 2008Faith E. Jacobsen Abstract The desire to inhibit zinc-dependent matrix metalloproteinases (MMPs) has, over the course of the last 30 years, led to the development of a plethora of MMP inhibitors that bind directly to the active-site metal. With one exception, all of these drugs have failed in clinical trials, due to many factors, including an apparent lack of specificity for MMPs. To address the question of whether these inhibitors are selective for MMPs in a biological setting, a cell-based screening method is presented to compare the relative activities of zinc, heme iron, and non-heme iron enzymes in the presence of these compounds using the RAW264.7 macrophage cell line. We screened nine different zinc-binding groups (ZBGs), four established MMP inhibitors (MMPis), and two novel MMP inhibitors developed in our laboratory to determine their selectivities against five different metalloenzymes. Using this model, we identified two nitrogen donor compounds,2,2,-dipyridylamine (DPA) and triazacyclononane (TACN),as the most selective ZBGs for zinc metalloenzyme inhibitor development. We also demonstrated that the model could predict known nonspecific interactions of some of the most commonly used MMPis, and could also give cross-reactivity information for newly developed MMPis. This work demonstrates the utility of cell-based assays in both the design and the screening of novel metalloenzyme inhibitors. [source] Synthesis, SAR, and Biological Evaluation of ,-Sulfonylphosphonic Acids as Selective Matrix Metalloproteinase InhibitorsCHEMMEDCHEM, Issue 3 2009Maria Teresa Rubino Dr. Abstract Selective MMP inhibitors: Eleven ,-sulfonylphosphonates were synthesized and tested as MMP inhibitors. The IC50 values for most of them are in the nanomolar range against MMP-2, -8, -13, and -14, with an interesting selectivity profile versus MMP-9. Eleven simple , -sulfonylphosphonates, new analogues of previously reported , -sulfonylaminophosphonates, were prepared and tested as MMP inhibitors. The IC50 values of most of these compounds are in the nanomolar range against MMP-2, -8, -13, and -14. Compound 11 proved to be the most effective inhibitor of MMP-2 (IC50=60,nM), with interesting selectivity versus the antitarget enzymes MMP-3 and MMP-9. The mode of binding of the new phosphonates in the active site of MMP-2 was studied, and variations in inhibition was explained by means of molecular modeling. [source] | ||||||||||||||||