ABSTRACT
Dolutegravir (DTG) is a first-line antiretroviral drug (ARV) used in combination therapy for the treatment of human immunodeficiency virus type-1 (HIV-1) infection. The drug is effective, safe, and well tolerated. Nonetheless, concerns have recently emerged for its usage in pregnant women or those of child-bearing age. Notably, DTG-based ARV regimens have been linked to birth defects seen as a consequence of periconceptional usages. To this end, uncovering an underlying mechanism for DTG-associated adverse fetal development outcomes has gained clinical and basic research interest. We now report that DTG inhibits matrix metalloproteinases (MMPs) activities that could affect fetal neurodevelopment. DTG is a broad-spectrum MMPs inhibitor and binds to Zn++ at the enzyme's catalytic domain. Studies performed in pregnant mice show that DTG readily reaches the fetal central nervous system during gestation and inhibits MMP activity. Postnatal screenings of brain health in mice pups identified neuroinflammation and neuronal impairment. These abnormalities persist as a consequence of in utero DTG exposure. We conclude that DTG inhibition of MMPs activities during gestation has the potential to affect prenatal and postnatal neurodevelopment.
Subject(s)
Anti-Retroviral Agents/toxicity , Heterocyclic Compounds, 3-Ring/toxicity , Matrix Metalloproteinase Inhibitors/toxicity , Neural Tube Defects/chemically induced , Neurodevelopmental Disorders/chemically induced , Neuroinflammatory Diseases/chemically induced , Oxazines/toxicity , Piperazines/toxicity , Pyridones/toxicity , Animals , Anti-Retroviral Agents/pharmacokinetics , Anti-Retroviral Agents/pharmacology , Brain/embryology , Brain/enzymology , Catalytic Domain/drug effects , Female , Gene Expression Profiling , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Heterocyclic Compounds, 3-Ring/pharmacology , Male , Matrix Metalloproteinase Inhibitors/pharmacokinetics , Matrix Metalloproteinase Inhibitors/pharmacology , Mice , Mice, Inbred C3H , Molecular Docking Simulation , Neural Tube Defects/embryology , Neuroimaging , Neuroinflammatory Diseases/embryology , Oxazines/pharmacokinetics , Oxazines/pharmacology , Piperazines/pharmacokinetics , Piperazines/pharmacology , Placenta/chemistry , Pregnancy , Pyridones/pharmacokinetics , Pyridones/pharmacology , Tissue Distribution , Zinc/metabolismABSTRACT
Osteoarthritis (OA) is a chronic disorder that causes damage to the cartilage and surrounding tissues and is characterized by pain, stiffness, and loss of function. Current treatments for OA primarily involve providing only relief of symptoms but does not affect the overall trajectory of the disease. A major goal for treating OA has been to slow down or reverse disease progression. Matrix metalloproteinase-13 (MMP-13) is expressed by chondrocytes and synovial cells in human OA and is thought to play a critical role in cartilage destruction. Herein we report a new, allosteric MMP-13 inhibitor, AQU-019, that has been optimized for potency, metabolic stability, and oral bioavailability through a combination of structure activity relationship (SAR) and deuterium substitution as a potential disease modifying OA drug (DMOAD). The inhibitor was demonstrated to be chondroprotective when injected intraarticular (IA) in the monoiodoacetic acid (MIA) rat model of OA.
Subject(s)
Matrix Metalloproteinase 13/chemistry , Matrix Metalloproteinase Inhibitors/therapeutic use , Osteoarthritis/drug therapy , Amides/chemistry , Amides/metabolism , Amides/therapeutic use , Animals , Disease Models, Animal , Half-Life , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Joints/pathology , Matrix Metalloproteinase 13/metabolism , Matrix Metalloproteinase Inhibitors/chemistry , Matrix Metalloproteinase Inhibitors/pharmacokinetics , Osteoarthritis/chemically induced , Osteoarthritis/pathology , Pyrimidines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
Introduction: Matrix MetalloProteinases (MMPs) are key enzymes in several pathophysiological processes connected to the extracellular matrix (ECM) degradation. Earlier clinical trials evaluating broad spectrum MMP inhibitors as cancer therapeutics failed to succeed, resulting in toxic side effects, such as musculoskeletal pain and inflammation, due to poor selectivity. As it is now recognized that some MMPs are essential for tumor progression and metastasis, but others play host-protective functions, selective MMP inhibitors are needed, and their interest has grown also for therapeutic applications beyond cancer, such as infectious, inflammatory and neurological diseases. Areas covered: This updated review describes patents concerning MMP inhibitors published within January 2014 and June 2020, with therapeutic applications spanning from cancer to inflammatory and neurological disorders. Expert opinion: Although the number of patents has decreased with respect to the previous decade, new applications provide selective matrix metalloproteinase inhibitors for therapeutic treatments beyond cancer. For several applications, the need of selective inhibitors resulted in the development of new non-hydroxamate compounds, paving the way towards a renewed interest towards MMPs as therapeutic targets. In particular, inhibitors able to cross the blood-brain barrier have been disclosed and proposed for the treatment of neurological conditions, infections, wound healing and cancer.
Subject(s)
Antineoplastic Agents/pharmacology , Matrix Metalloproteinase Inhibitors/pharmacology , Neoplasms/drug therapy , Animals , Blood-Brain Barrier/metabolism , Drug Design , Drug Development , Humans , Matrix Metalloproteinase Inhibitors/adverse effects , Matrix Metalloproteinase Inhibitors/pharmacokinetics , Neoplasms/enzymology , Patents as Topic , Tissue DistributionABSTRACT
BACKGROUND AND OBJECTIVES: Matrix metalloproteinases (MMPs) are proteases with different biological and pathological activities, and many have been linked to several diseases. Targeting individual MMPs may offer a safer therapeutic potential for several diseases. We assessed the safety, tolerability, and pharmacokinetics of FP-025, a novel, highly selective oral matrix metalloproteinase-12 inhibitor, in healthy subjects. METHODS: Two randomized, double-blind, placebo-controlled studies were conducted. Study I was a first-in-man study, evaluating eight single ascending doses (SADs) (50-800 mg) in two formulations: i.e., neat FP-025 in capsule (API-in-Capsule) and in an amorphous solid dispersion (ASD-in-Capsule) formulation. In Study II, three multiple ascending doses (MADs) (100, 200, and 400 mg, twice daily) of FP-025 (ASD-in-Capsule) were administered for 8 days, including a food-effect evaluation. RESULTS: Ninety-six subjects were dosed. Both formulations were well tolerated with one adverse event (AE) reported in the 800 mg API-in-Capsule SAD group and seven AEs throughout the MAD groups. The exposure to FP-025 was low with the API-in-Capsule formulation; it increased dose-dependently with the ASD-in-Capsule formulation, with which exposure to FP-025 increased in a greater-than-dose-proportional manner at lower doses (≤ 100 mg) but less proportionally at higher doses. The elimination half-life (t1/2) was between 6 (Study I) and 8 h (Study II). Accumulation of FP-025 was approximately 1.7-fold in the MAD study. Food intake delayed the rate of absorption, but without effect in the extent of absorption or bioavailability. CONCLUSION: FP-025 was well tolerated and showed a favorable pharmacokinetic profile following ASD-in-Capsule dosing. Efficacy studies in target patient populations, including asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis, are warranted. TRIAL REGISTRATION NUMBER: www.clinicaltrials.gov : NCT02238834 (Study I); NCT03304964 (Study II). Trial registration date: Study I was registered on 12 September 2014 while study II was registered on 9 October 2017.
Subject(s)
Matrix Metalloproteinase 12/drug effects , Matrix Metalloproteinase Inhibitors/administration & dosage , Adult , Area Under Curve , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Male , Matrix Metalloproteinase Inhibitors/adverse effects , Matrix Metalloproteinase Inhibitors/pharmacokinetics , Young AdultABSTRACT
An intra-hippocampus injection of kainic acid serves as a model of status epilepticus and the subsequent development of temporal lobe epilepsy. Matrix metalloproteinase-9 (MMP-9) is an enzyme that controls remodeling of the extracellular milieu under physiological and pathological conditions. In response to brain insult, MMP-9 contributes to pathological synaptic plasticity that may play a role in the progression of an epileptic condition. Marimastat is a metalloproteinase inhibitor that was tested in clinical trials of cancer. The present study assessed whether marimastat can impair the development of epilepsy. The inhibitory efficacy of marimastat was initially tested in neuronal cultures in vitro. As a marker substrate, we used nectin-3. Next, we investigated the blood-brain barrier penetration of marimastat using mass spectrometry and evaluated the therapeutic potential of marimastat against seizure outcomes. We found that marimastat inhibited the cleavage of nectin-3 in hippocampal neuronal cell cultures. Marimastat penetrated the blood-brain barrier and exerted an inhibitory effect on metalloproteinase activity in the brain. Finally, marimastat decreased some seizure parameters, such as seizure score and number, but did not directly affect status epilepticus. The long-term effects of marimastat were evident up to 6 weeks after kainic acid administration, in which marimastat still inhibited seizure duration.
Subject(s)
Hydroxamic Acids/therapeutic use , Matrix Metalloproteinase Inhibitors/therapeutic use , Status Epilepticus/drug therapy , Animals , Blood-Brain Barrier/metabolism , Disease Models, Animal , Drug Evaluation, Preclinical , Hydroxamic Acids/pharmacokinetics , Kainic Acid , Male , Matrix Metalloproteinase 9/metabolism , Matrix Metalloproteinase Inhibitors/pharmacokinetics , Mice, Inbred C57BL , Nectins/metabolismABSTRACT
Chronic obstructive pulmonary disease (COPD) is a lung disorder characterized by progressive airflow obstruction associated with inflammation and emphysema, and it is currently one of the leading causes of death worldwide. Recent studies with genetically engineered mice reported that during pulmonary inflammation, basophil-derived interleukin-4 can act on lung-infiltrating monocytes causing aberrant expression of the matrix metalloproteinase-12 (MMP-12). MMP-12 activity in turn causes the destruction of alveolar walls leading to emphysema, making it potentially a valid target for pharmacological intervention. Using nuclear magnetic resonance (NMR)- and structure-based optimizations, the current study reports on the optimized novel, potent, and selective MMP-12 inhibitors with single-digit nanomolar affinity in vitro and in vivo efficacy. Using a murine model of elastase-induced emphysema we demonstrated that the most potent agents exhibited a significant decrease in emphysema-like pathology compared to vehicle-treated mice, thus suggesting that the reported agents may potentially be translated into novel therapeutics for the treatment of COPD.
Subject(s)
Matrix Metalloproteinase 12/metabolism , Matrix Metalloproteinase Inhibitors/chemistry , Animals , Binding Sites , Crystallography, X-Ray , Disease Models, Animal , Emphysema/drug therapy , Emphysema/etiology , Half-Life , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Matrix Metalloproteinase 12/chemistry , Matrix Metalloproteinase Inhibitors/pharmacokinetics , Matrix Metalloproteinase Inhibitors/therapeutic use , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Molecular Dynamics Simulation , Nuclear Magnetic Resonance, Biomolecular , Pancreatic Elastase/metabolism , Peptides/genetics , Peptides/metabolism , Peptides/therapeutic use , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/pathology , Structure-Activity RelationshipABSTRACT
Matrix metalloproteinases are enzymes that degrade the extracellular matrix. They have different substrates but similar structural organization. Matrix metalloproteinases are involved in many physiological and pathological processes and there is a need to develop inhibitors for these enzymes in order to modulate the degradation of the extracellular matrix (ECM). There exist two classes of inhibitors: endogenous and synthetics. The development of synthetic inhibitors remains a great challenge due to the low selectivity and specificity, side effects in clinical trials, and instability. An extensive review of currently reported synthetic inhibitors and description of their properties is presented.
Subject(s)
Matrix Metalloproteinase Inhibitors/chemistry , Matrix Metalloproteinases/metabolism , Tissue Inhibitor of Metalloproteinases/metabolism , Animals , Drug Discovery/methods , Humans , Matrix Metalloproteinase Inhibitors/adverse effects , Matrix Metalloproteinase Inhibitors/pharmacokinetics , Tissue Inhibitor of Metalloproteinases/chemistryABSTRACT
BACKGROUND: The main aim of this work was to develop stable (>2 years) doxycycline formulation, at clinically relevant concentrations and using clinically relevant formulation. Doxycycline has a MMP- inhibitory effects that is important for the treatment of various oral mucosal conditions. Therefore, protecting doxycycline from degradation in aqueous formulation requires halting or prevention of oxidation and epimerisation of the active compound. METHODS: Stabilizing excipients were intuitively put together to enhance the stability as a cumulative effort. A total of 30 hydrogels were compared with different types and concentrations of stability enhancing excipients, pH, storage temperatures (4, 25 and 40°C) and mucoadhesive polymers. The duration of the study was from day 1 and up to 58 months. The gelation temperature was adjusted below the actual body temperature. The complexation efficiency between the doxycycline and HPßCD was studied using the DSC, FTIR and XRPD. RESULTS: The majority of formulations at 4°C were highly stable by the end of 58 months and their stabilities were improved at all 3 temperatures. CONCLUSION: In conclusion, it is possible to prevent doxycycline from both oxidation and epimerization in an aqueous formulation, for up to 5 years.
Subject(s)
Doxycycline/administration & dosage , Excipients/chemistry , Matrix Metalloproteinase Inhibitors/administration & dosage , Stomatitis, Aphthous/drug therapy , 2-Hydroxypropyl-beta-cyclodextrin/chemistry , Adhesiveness , Administration, Mucosal , Chemistry, Pharmaceutical , Doxycycline/chemistry , Doxycycline/pharmacokinetics , Drug Stability , Hydrogels/chemistry , Hydrogen-Ion Concentration , Matrix Metalloproteinase Inhibitors/chemistry , Matrix Metalloproteinase Inhibitors/pharmacokinetics , Matrix Metalloproteinases/metabolism , Mouth Mucosa/chemistry , Mouth Mucosa/drug effects , Mouth Mucosa/immunology , Mouth Mucosa/metabolism , Oxidation-Reduction , Signal Transduction/drug effects , Signal Transduction/immunology , Stomatitis, Aphthous/immunology , Stomatitis, Aphthous/pathology , Water/chemistryABSTRACT
Aim: A breakthrough in modern medicine, in terms of treatment of Alzheimer's disease, is yet to be seen, as the scene is currently plagued with numerous clinical trial failures. Here, we are exploring multifunctional hybrid sulfonamides for their anti-Alzheimer activity due to the complex nature of the disease. Results & methodology: Compound 41 showed significant inhibition of MMP-2 (IC50: 18.24 ± 1.62 nM), AChE (IC50: 4.28 ± 0.15 µM) and BuChE (IC50: 1.32 ± 0.02 µM). It also exhibited a metal-chelating property, as validated by an in vitro metal-induced Aß aggregation assay using confocal fluorescence imaging. Whereas, MTT and DPPH assays revealed it to be nontoxic and neuroprotective with substantial antioxidant property. Conclusion: The present study puts forth potent yet nontoxic lead molecules, which foray into the field of multitargeted agents for the treatment of Alzheimer's disease.
Subject(s)
Alzheimer Disease/drug therapy , Chelating Agents/therapeutic use , Cholinesterase Inhibitors/therapeutic use , Matrix Metalloproteinase Inhibitors/therapeutic use , Sulfonamides/therapeutic use , Acetylcholinesterase/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Animals , Butyrylcholinesterase/metabolism , Cell Survival/drug effects , Chelating Agents/chemistry , Chelating Agents/pharmacokinetics , Chlorocebus aethiops , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacokinetics , Computer Simulation , Disease Models, Animal , Humans , Male , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase Inhibitors/chemistry , Matrix Metalloproteinase Inhibitors/pharmacokinetics , Maze Learning/drug effects , Molecular Docking Simulation , Molecular Structure , Rats , Rats, Wistar , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Vero CellsABSTRACT
Matrix metalloproteinase-12 (MMP-12) is highly upregulated in several inflammatory diseases, including abdominal aortic aneurysm (AAA). Here we report four novel 99mTc-labeled radiotracers derived from a highly selective competitive MMP-12 inhibitor. These tracers in their 99gTc version were assessed in vitro on a set of human metalloproteases and displayed high affinity and selectivity toward MMP-12. Their radiolabeling with 99mTc was shown to be efficient and stable in both buffer and mouse blood. The tracers showed major differences in their biodistribution and blood clearance. On the basis of its in vivo performance, [99mTc]-1 was selected for evaluation in murine AAA, where MMP-12 gene expression is upregulated. Autoradiography of aortae at 2 h postinjection revealed high uptake of [99mTc]-1 in AAA relative to adjacent aorta. Tracer uptake specificity was demonstrated through in vivo competition. This study paves the way for further evaluation of [99mTc]-1 for imaging AAA and other MMP-12-associated diseases.
Subject(s)
Aorta/diagnostic imaging , Matrix Metalloproteinase 12/metabolism , Matrix Metalloproteinase Inhibitors/chemistry , Molecular Imaging/methods , Organotechnetium Compounds/chemistry , Animals , Aortic Aneurysm, Abdominal/diagnostic imaging , Humans , Male , Matrix Metalloproteinase Inhibitors/pharmacokinetics , Mice , Mice, Inbred C57BL , Radioactive Tracers , Radiochemistry , Tissue Distribution , Up-RegulationABSTRACT
Global prevalence of the severe periodontitis is at the alarming stage and its association with the systemic complications is highly evident which cannot be neglected. An insight into the pathophysiology of the periodontitis reveals that the promising amelioration could only be envisaged with the 4-D/multi-pronged approach of combining antibiotic along with the host modulating agents. The complications of the disease itself suggest that the use of antibiotic alone is not able to cater the symptoms completely. There is a need of other host modulatory agents too, such as Cyclo-oxygenase -II (COX II) enzyme inhibitors, Matrix metalloproteinase's (MMPs) inhibitors and osteo-integrating agents. Also, there is an unmet need of singular treatment modality through which all these agents can be sequentially and directly delivered into the periodontal cavity. The current hypothesis takes it a step forward wherein an antibiotic is combined with other three host modulatory agents in a singular drug delivery system. The encapsulation of multiple therapeutic agents with controlled release would therefore allow for reduced drug dose thus minimizing side effects; contributing to enhanced patient compliance and treatment efficacy. Hence this approach can be presented as a 4-D/multi-pronged approach for circumvention of periodontitis.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Cyclooxygenase Inhibitors/therapeutic use , Matrix Metalloproteinase Inhibitors/therapeutic use , Periodontitis/drug therapy , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Celecoxib/administration & dosage , Celecoxib/therapeutic use , Combined Modality Therapy , Cyclooxygenase Inhibitors/administration & dosage , Cyclooxygenase Inhibitors/pharmacokinetics , Doxycycline/administration & dosage , Doxycycline/therapeutic use , Drug Administration Schedule , Drug Synergism , Drug Therapy, Combination , Durapatite/administration & dosage , Durapatite/therapeutic use , Gingiva/physiology , Humans , Matrix Metalloproteinase Inhibitors/administration & dosage , Matrix Metalloproteinase Inhibitors/pharmacokinetics , Minocycline/administration & dosage , Minocycline/therapeutic use , Models, Biological , Osseointegration/drug effects , Periodontics/methods , Periodontitis/surgery , Regeneration , Substance-Related DisordersABSTRACT
Matrix metalloproteinases (MMPs) are a family of zinc- and calcium-dependent endopeptidases which are secreted or anchored in the cell membrane and are capable of degrading the multiple components of the extracellular matrix (ECM). MMPs are frequently overexpressed or highly activated in numerous human diseases. Owing to the important role of MMPs in human diseases, many MMP inhibitors (MMPIs) have been developed as novel therapeutics, and some of them have entered clinical trials. However, so far, only one MMPI (doxycycline) has been approved by the FDA. Therefore, the evaluation of the activity of a specific subset of MMPs in human diseases using clinically relevant imaging techniques would be a powerful tool for the early diagnosis and assessment of the efficacy of therapy. In recent years, numerous MMPIs labeled imaging agents have emerged. This article begins by providing an overview of the MMP subfamily and its structure and function. The latest advances in the design of subtype selective MMPIs and their biological evaluation are then summarized. Subsequently, the potential use of MMPI-labeled diagnostic agents in clinical imaging techniques are discussed, including positron emission tomography (PET), single-photon emission computed tomography (SPECT) and optical imaging (OI). Finally, this article concludes with future perspectives and clinical utility.
Subject(s)
Atherosclerosis/diagnostic imaging , Cardiovascular Diseases/diagnostic imaging , Lung Diseases/diagnostic imaging , Matrix Metalloproteinase Inhibitors/pharmacokinetics , Matrix Metalloproteinases/chemistry , Molecular Probes/pharmacokinetics , Neoplasms/diagnostic imaging , Osteoarthritis/diagnostic imaging , Animals , Atherosclerosis/metabolism , Atherosclerosis/pathology , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/pathology , Catalytic Domain/genetics , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/diagnostic imaging , Encephalomyelitis, Autoimmune, Experimental/metabolism , Encephalomyelitis, Autoimmune, Experimental/pathology , Extracellular Matrix/metabolism , Extracellular Matrix/pathology , Humans , Lung Diseases/metabolism , Lung Diseases/pathology , Matrix Metalloproteinase Inhibitors/chemical synthesis , Matrix Metalloproteinases/genetics , Matrix Metalloproteinases/metabolism , Molecular Imaging/methods , Molecular Probes/chemical synthesis , Multiple Sclerosis/diagnostic imaging , Multiple Sclerosis/metabolism , Multiple Sclerosis/pathology , Neoplasms/metabolism , Neoplasms/pathology , Osteoarthritis/metabolism , Osteoarthritis/pathology , Positron-Emission Tomography/methods , Tomography, Emission-Computed, Single-Photon/methodsABSTRACT
The study was aimed to evaluate the effectiveness of rosmarinic acid (RA) loaded ethosomes (ETHs) and liposomes (LPs) when subjected to the transdermal application. RA-loaded ETHs and LPs were prepared, optimised, and characterised. The ex vivo permeation studies of formulations using mouse abdominal skin were performed. Antioxidant activities and the inhibitory effects of formulations on collagenase and elastase enzymes were measured. Optimised ethosomal formulation (F3) was showed nanometric size range (138 ± 1.11 nm) and greatest entrapment (55 ± 1.80%), was selected for further transdermal permeation studies. Skin permeation profile of the nanoformulations analysed by HPLC revealed an enhanced permeation of ETHs. Transdermal flux of ETHs was found to be higher than RA solution and LPs. Enzyme inhibitions of ETHs were the significant difference found between ETHs and LPs (p < 0.05). ETHs were found to be more effective and successful than LPs. Results suggest that ETHs are more effective than LPs for transdermal delivery of RA.
Subject(s)
Antioxidants/administration & dosage , Cinnamates/administration & dosage , Depsides/administration & dosage , Drug Carriers/chemistry , Matrix Metalloproteinase Inhibitors/administration & dosage , Administration, Cutaneous , Animals , Antioxidants/pharmacokinetics , Antioxidants/pharmacology , Cell Line , Cinnamates/pharmacokinetics , Cinnamates/pharmacology , Collagenases/metabolism , Depsides/pharmacokinetics , Depsides/pharmacology , Liposomes/chemistry , Matrix Metalloproteinase Inhibitors/pharmacokinetics , Matrix Metalloproteinase Inhibitors/pharmacology , Mice , Pancreatic Elastase/antagonists & inhibitors , Pancreatic Elastase/metabolism , Skin/drug effects , Skin/metabolism , Skin Absorption , Skin Aging/drug effects , Rosmarinic AcidABSTRACT
Recruitment of liver sinusoidal endothelial cell progenitor cells (sprocs) from the bone marrow by vascular endothelial growth factor-stromal cell-derived factor-1 (VEGF-sdf-1) signaling promotes recovery from injury and drives liver regeneration. Matrix metalloproteinases (MMPs) can proteolytically cleave VEGF, which might inhibit progenitor cell recruitment, but systemic matrix metalloproteinase inhibition might prevent efflux of progenitors from the bone marrow. The hypothesis for this study was that liver-selective MMP-9 inhibition would protect the hepatic VEGF-sdf-1 signaling pathway, enhance bone marrow sproc recruitment, and thereby ameliorate liver injury and accelerate liver regeneration, whereas systemic MMP inhibition would impair bone marrow sproc mobilization and therefore have less benefit or be detrimental. We found that liver-selective MMP-9 inhibition accelerated liver regeneration after partial hepatectomy by 40%, whereas systemic MMP inhibition impaired liver regeneration. Liver-selective MMP-9 inhibition largely abolished warm ischemia-reperfusion injury. In the extended hepatectomy model, liver-selective MMP-9 inhibition restored liver sinusoidal endothelial cell integrity, enhanced liver regeneration, and reduced ascites. Liver-selective MMP-9 inhibition markedly increased recruitment and engraftment of bone marrow sprocs, whereas systemic MMP inhibition impaired mobilization of bone marrow sprocs and their hepatic engraftment. Hepatic MMP-9 proteolytically cleaved VEGF after partial hepatectomy. Liver-selective MMP-9 inhibition prevented VEGF cleavage and doubled protein expression of VEGF and its downstream signaling partner sdf-1. In contrast, systemic MMP inhibition enhanced recruitment and engraftment of infused allogeneic progenitors. Conclusion: Liver-selective MMP inhibition prevents proteolytic cleavage of hepatic VEGF, which enhances recruitment and engraftment of bone marrow sprocs after liver injury. This ameliorates injury and accelerates liver regeneration. Liver-selective MMP-9 inhibition may be a therapeutic tool for liver injury that damages the vasculature, whereas systemic MMP inhibition can enhance the benefit of stem cell therapy with endothelial progenitor cells.
Subject(s)
Liver Regeneration/drug effects , Liver/blood supply , Matrix Metalloproteinase 9/drug effects , Matrix Metalloproteinase Inhibitors/pharmacokinetics , Matrix Metalloproteinase Inhibitors/therapeutic use , Oligonucleotides, Antisense/pharmacology , Oligonucleotides, Antisense/therapeutic use , Reperfusion Injury/prevention & control , Animals , Male , Matrix Metalloproteinase 9/physiology , Rats , Rats, Inbred Lew , Time FactorsABSTRACT
A structure-activity/structure-property relationship study based on the physicochemical as well as in vitro pharmacokinetic properties of a first generation matrix metalloproteinase (MMP)-13 inhibitor (2) was undertaken. After systematic variation of inhibitor 2, compound 31 was identified which exhibited microsomal half-life higher than 20â¯min, kinetic solubility higher than 20⯵M, and a permeability coefficient greater than 20â¯×â¯10-6â¯cm/s. Compound 31 also showed excellent in vivo PK properties after IV dosing (Cmaxâ¯=â¯56.8⯵M, T1/2 (plasma)â¯=â¯3.0â¯h, Clâ¯=â¯0.23â¯mL/min/kg) and thus is a suitable candidate for in vivo efficacy studies in an OA animal model.
Subject(s)
Matrix Metalloproteinase 13/drug effects , Matrix Metalloproteinase Inhibitors/chemistry , Matrix Metalloproteinase Inhibitors/pharmacology , Animals , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Half-Life , Humans , Inhibitory Concentration 50 , Kinetics , Matrix Metalloproteinase Inhibitors/pharmacokinetics , Mice , Microsomes, Liver/metabolism , Models, Animal , Rats , Solubility , Structure-Activity RelationshipABSTRACT
Targeting matrix metalloproteinases (MMPs) is a pursued strategy for treating several pathological conditions, such as multiple sclerosis and cancer. Herein, a series of novel tetrahydro-ß-carboline derivatives with outstanding inhibitory activity toward MMPs are present. In particular, compounds 9 f, 9 g, 9 h and 9 i show sub-nanomolar IC50 values. Interestingly, compounds 9 g and 9 i also provide remarkable selectivity toward gelatinases; IC50 =0.15â nm for both toward MMP-2 and IC50 =0.63 and 0.58â nm, respectively, toward MMP-9. Molecular docking simulations, performed by employing quantum mechanics based partial charges, shed light on the rationale behind binding involving specific interactions with key residues of S1' and S3' domains. Taken together, these studies indicate that tetrahydro-ß-carboline represents a promising scaffold for the design of novel inhibitors able to target MMPs and selectively bias gelatinases, over the desirable range of the pharmacokinetics spectrum.
Subject(s)
Carbolines/chemistry , Gelatinases/antagonists & inhibitors , Matrix Metalloproteinase Inhibitors/chemistry , Carbolines/chemical synthesis , Carbolines/pharmacokinetics , Drug Design , Enzyme Assays , Gelatinases/chemistry , Humans , Matrix Metalloproteinase 2/chemistry , Matrix Metalloproteinase 9/chemistry , Matrix Metalloproteinase Inhibitors/chemical synthesis , Matrix Metalloproteinase Inhibitors/pharmacokinetics , Molecular Docking Simulation , StereoisomerismABSTRACT
Treatment for metastatic cancer is a great challenge throughout the world. Commonly, directed inhibition of extracellular matrix metalloproteinases (MMPs) secreted by cancer cells can reduce metastasis. Here, a novel nanoplatform (HPMC NPs) assembled from hyaluronic acid (HA)-paclitaxel (PTX) prodrug and marimastat (MATT)/ß-casein (CN) complexes was established to cure a 4T1 metastatic cancer model via targeting CD44 and intracellular, rather than extracellular, MMPs. Methods: HPMC NPs were prepared by assembling the complexes and prodrug under ultrasonic treatment, which the interaction between them was evaluated by förster resonance energy transfer, circular dichroism and fluorescence spectra. The developed nanoplatform was characterized via dynamic light scattering and transmission electron microscopy, and was evaluated in terms of MMP-sensitive release and stability. Subsequently, the cellular uptake, trafficking, and in vitro invasion were studied by flow cytometry, confocal laser microscopy and transwell assay. MMP expression and activity was determined by western blotting and gelatin zymography. Finally, the studies of biodistribution and antitumor efficacy in vivo were performed in a mouse 4T1 tumor breast model, followed by in vivo safety study in normal mouse. Results: The interaction between the prodrug and complexes is strong with a high affinity, resulting in the assembly of these two components into hybrid nanoparticles (250 nm). Compared with extracellular incubation with MATT, HPMC NP treatment markedly reduced the expression (100%) and activity (50%) of MMPs in 4T1 cells and in the tumor. HPMC NPs exhibited 1.4-fold tumor accumulation, inhibited tumor-growth by >8-fold in volume with efficient apoptosis and proliferation, and suppressed metastasis (>5-fold) and angiogenesis (>3-fold). Overall, HPMC NPs were efficient in metastatic cancer therapy. Conclusions: According to the assembly of polymer prodrug and protein-drug complexes, this study offers a new strategy for constructing nanoparticles for targeted drug delivery, biomedical imaging, and combinatorial treatment. Importantly, via inhibition of intracellular MMPs, metastasis and angiogenesis can be potently blocked, benefiting the rational design of nanomedicine for cancer treatment.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Mammary Neoplasms, Experimental/drug therapy , Matrix Metalloproteinase Inhibitors/therapeutic use , Neovascularization, Pathologic/drug therapy , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/pharmacokinetics , Animals , Caseins/metabolism , Cell Line, Tumor , Drug Liberation , Female , Hyaluronic Acid/analogs & derivatives , Hydroxamic Acids/administration & dosage , Hydroxamic Acids/therapeutic use , Mammary Neoplasms, Experimental/pathology , Matrix Metalloproteinase Inhibitors/administration & dosage , Matrix Metalloproteinase Inhibitors/pharmacokinetics , Matrix Metalloproteinases/metabolism , Mice , Mice, Inbred BALB C , Nanoconjugates/chemistry , Neoplasm Metastasis , Paclitaxel/administration & dosage , Paclitaxel/therapeutic use , Prodrugs/administration & dosage , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Protein BindingABSTRACT
BACKGROUND AND AIMS: Matrix metalloproteinase-9 [MMP9] is implicated in the pathogenesis of ulcerative colitis [UC] via disruption of intestinal barrier integrity and function. A phase 2/3 combined trial was designed to examine the efficacy, safety, and pharmacokinetics of the anti-MMP9 antibody, andecaliximab [formerly GS-5745], in patients with moderately to severely active UC. METHODS: Patients were randomised [1:1:1] to receive placebo, 150 mg andecaliximab every 2 weeks [Q2W], or 150 mg andecaliximab weekly [QW], via subcutaneous administration. The primary endpoint was endoscopy/bleeding/stool [EBS]-defined clinical remission [endoscopic subscore of 0 or 1, rectal bleeding subscore of 0, and at least a 1-point decrease from baseline in stool frequency to achieve a subscore of 0 or 1] at Week 8. The phase 2/3 trial met prespecified futility criteria and was terminated before completion. This study describes results from the 8-week induction phase. RESULTS: Neither 150 mg andecaliximab Q2W or QW resulted in a significant increase vs placebo in the proportion of patients achieving EBS clinical remission at Week 8. Remission rates [95% confidence intervals] were 7.3% [2.0%-17.6%], 7.4% [2.1%-17.9%], and 1.8% [0.0%-9.6%] in the placebo, andecaliximab Q2W, and andecaliximab QW groups, respectively. Similarly, Mayo Clinic Score response, endoscopic response, and mucosal [histological] healing did not differ among groups. Rates of adverse events were comparable among andecaliximab and placebo. CONCLUSIONS: Eight weeks of induction treatment with 150 mg andecaliximab in patients with UC did not induce clinical remission or response. Andecaliximab was well tolerated and pharmacokinetic properties were consistent with those previously reported.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Colitis, Ulcerative/drug therapy , Matrix Metalloproteinase Inhibitors/therapeutic use , Adult , Antibodies, Monoclonal, Humanized/pharmacokinetics , Double-Blind Method , Drug Administration Schedule , Female , Humans , Male , Matrix Metalloproteinase 9 , Matrix Metalloproteinase Inhibitors/pharmacokinetics , Middle Aged , Remission Induction , Treatment OutcomeABSTRACT
Dysregulated levels of activated matrix metalloproteinases (MMPs) are linked to different pathologies, such as cancer, atherosclerosis, neuroinflammation, and arthritis. Therefore, imaging of MMPs with positron-emission tomography (PET) represents a powerful tool for the diagnosis of MMP-associated diseases. Moreover, to distinguish between the distinct functions and roles of individual MMPs in particular pathophysiological processes, their specific imaging must be realized with radiolabeled tracers, such as fluorine-18-labeled MMP inhibitors (MMPIs). Therefore, fluorinated dibenzofuransulfonamide-based MMPIs showing excellent inhibition of MMP-12 and selectivity for MMP-12 over other MMPs were prepared. MMP-12 is a key enzyme in diseases such as chronic obstructive pulmonary disease (COPD) and atherosclerosis. Because of their promising in vitro properties, three candidates (4, 9, and 19) were selected from this library, and radiofluorinated analogues ([18F]4, [18F]9, and [18F]19) were successfully synthesized. Initial in vitro serum stability and in vivo biodistribution studies of the radiolabeled MMPIs with PET demonstrated their potential benefit for preferable MMP-12 imaging.
Subject(s)
Drug Design , Matrix Metalloproteinase 12/metabolism , Matrix Metalloproteinase Inhibitors/chemical synthesis , Matrix Metalloproteinase Inhibitors/pharmacology , Positron-Emission Tomography/methods , Animals , Chemistry Techniques, Synthetic , Humans , Male , Matrix Metalloproteinase Inhibitors/chemistry , Matrix Metalloproteinase Inhibitors/pharmacokinetics , Mice , Mice, Inbred C57BL , Radioactive Tracers , Radiochemistry , Tissue DistributionABSTRACT
PURPOSE: Andecaliximab (GS-5745) is a highly selective monoclonal antibody against matrix metalloproteinase-9 (MMP9), a proteolytic enzyme implicated in the pathogenesis of rheumatoid arthritis (RA). This study assessed the safety and pharmacokinetic (PK) parameters of andecaliximab in patients with RA and evaluated the effects of andecaliximab treatment on exploratory disease biomarkers. METHODS: In this double-blind, Phase 1b trial, patients with active RA were randomized (4:1) to receive 400-mg andecaliximab or placebo every 2 weeks for a total of 3 intravenous infusions. The primary and secondary end points were safety and the PK parameters of andecaliximab, respectively. Data were summarized by using descriptive statistics. FINDINGS: A total of 18 patients were randomized; 15 received andecaliximab (participants with confirmed RA diagnosis without current administration of a biologic DMARD a biologic DMARD (disease-modifying antirheumatic drug), aged 18 to 70 years old, weighing >45 to <120 kg). No deaths, serious adverse events, or study discontinuations occurred. All reported adverse events were grade 1 or grade 2 in severity. Mean plasma andecaliximab exposure was 587 d · µg/mL and 878 d · µg/mL at days 1 and 29, respectively, suggesting moderate accumulation. The median terminal t1/2 was 5.65 days; mean volume of distribution at steady state was 4560 mL. Mean MMP9 coverage (the percentage of total plasma MMP9 bound by therapeutic antibody) was maintained at ~80% after the first administration of andecaliximab. IMPLICATIONS: Andecaliximab administered as 3 infusions over 29 days was generally safe and well tolerated in patients with RA. The majority of total plasma MMP9 was bound by andecaliximab after the first administration. Clinical studies of increased treatment duration in larger patient cohorts are warranted. ClinicalTrials.gov identifier: NCT02176876. Registered on 25 June 2014.