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1.
Int J Mol Sci ; 20(4)2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30769782

RESUMO

There is an unmet medical need for the development of non-addicting pain therapeutics with enhanced efficacy and tolerability. The current study examined the effects of AQU-118, an orally active inhibitor of metalloproteinase-2 (MMP-2) and MMP-9, in the spinal nerve ligation (SNL) rat model of neuropathic pain. Mechanical allodynia and the levels of various biomarkers were examined within the dorsal root ganglion (DRG) before and after oral dosing with AQU-118. The rats that received the SNL surgery exhibited significant mechanical allodynia as compared to sham controls. Animals received either vehicle, positive control (gabapentin), or AQU-118. After SNL surgery, the dorsal root ganglion (DRG) of those rats dosed with vehicle had elevated messenger RNA (mRNA) expression levels for MMP-2, IL1-ß & IL-6 and elevated protein levels for caspase-3 while exhibiting decreased protein levels for myelin basic protein (MBP) & active IL-ß as compared to sham controls. Rats orally dosed with AQU-118 exhibited significantly reduced mechanical allodynia and decreased levels of caspase-3 in the DRG as compared to vehicle controls. Results demonstrate that oral dosing with the dual active, MMP-2/-9 inhibitor, AQU-118, attenuated mechanical allodynia while at the same time significantly reduced the levels of caspase-3 in the DRG.


Assuntos
Caspase 3/genética , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Neuralgia/tratamento farmacológico , Animais , Biomarcadores/metabolismo , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Indóis/administração & dosagem , Ligadura , Inibidores de Metaloproteinases de Matriz/administração & dosagem , Neuralgia/genética , Neuralgia/patologia , Propionatos/administração & dosagem , Ratos , Nervos Espinhais/efeitos dos fármacos , Nervos Espinhais/lesões , Tiofenos/administração & dosagem
2.
Eur J Med Chem ; 224: 113666, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34245949

RESUMO

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.


Assuntos
Metaloproteinase 13 da Matriz/química , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Osteoartrite/tratamento farmacológico , Amidas/química , Amidas/metabolismo , Amidas/uso terapêutico , Animais , Modelos Animais de Doenças , Meia-Vida , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Articulações/patologia , Metaloproteinase 13 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/química , Inibidores de Metaloproteinases de Matriz/farmacocinética , Osteoartrite/induzido quimicamente , Osteoartrite/patologia , Pirimidinas/química , Ratos , Relação Estrutura-Atividade
3.
J Oral Facial Pain Headache ; 29(3): 286-96, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26244437

RESUMO

AIMS: To study the effects of a novel matrix metalloproteinase-2 (MMP-2) and MMP-9 inhibitor, AQU-118, on mechanical allodynia in the spinal nerve ligation (SNL) model of neuropathic pain and the chronic constriction injury of the infraorbital nerve (CCI-IoN) model of neuropathic orofacial pain. METHODS: Five groups of SNL rats were given daily oral doses of AQU-118 (5, 10, 20 mg/kg), gabapentin (100 mg/kg), or vehicle (0.5% methylcellulose) and then paw withdrawal threshold was measured with von Frey filaments (VF). Three groups of CCI-IoN rats were given daily oral doses of either AQU-118 (40 mg/kg), gabapentin (100 mg/kg), or vehicle (0.5% methylcellulose) and then mechanical allodynia was measured with facial VF and non-reflex-based orofacial stimulation test (OFST) assay. Naïve rats were also tested for the effect of AQU-118 (40 mg/kg) on basal sensitivity to mechanical stimulation/locomotive activity. RESULTS: Mechanical allodynia in SNL rats was attenuated by gabapentin (100 mg/kg) and AQU-118 (in a dose-dependent manner). Mechanical allodynia in CCI-IoN rats was also attenuated (in an equipotent manner) by both AQU-118 (40 mg/ kg) and gabapentin (100 mg/kg) as measured by both facial VF and OFST assay. Upon cessation of either AQU-118 or gabapentin, VF-related responses in both models and OFST assay times reverted to levels observed in vehicle-treated rats. No statistically significant change was observed in locomotive activity/paw withdrawal threshold by AQU-118 (40 mg/kg) in naïve rats. CONCLUSION: The results demonstrated that oral AQU-118 attenuates mechanical allodynia in both neuropathic pain models and with efficacies that mirror gabapentin at the 40 mg/kg dose used in the CCI-IoN model but without effect on basal sensitivity to mechanical stimulation/locomotive activity. These findings support a possible role for MMP-2/-9 in the etiology of neuropathic pain and also suggest that inhibition strategies represent a viable treatment option.


Assuntos
Aminas/uso terapêutico , Ácidos Cicloexanocarboxílicos/uso terapêutico , Hiperalgesia/tratamento farmacológico , Indóis/uso terapêutico , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Neuralgia/tratamento farmacológico , Propionatos/uso terapêutico , Tiofenos/uso terapêutico , Ácido gama-Aminobutírico/uso terapêutico , Administração Oral , Animais , Modelos Animais de Doenças , Gabapentina , Metaloproteinase 2 da Matriz , Ratos , Ratos Sprague-Dawley , Nervos Espinhais , Nervo Trigêmeo
4.
Arthritis Rheum ; 60(7): 2008-18, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19565489

RESUMO

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-1alpha- 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.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Inibidores de Metaloproteinases de Matriz , Sistema Musculoesquelético/patologia , Osteoartrite/tratamento farmacológico , Animais , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Cartilagem Articular/cirurgia , Bovinos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Humanos , Interleucina-1alfa/farmacologia , Iodoacetatos/farmacologia , Iodoacetatos/uso terapêutico , Ácido Iodoacético/efeitos adversos , Masculino , Sistema Musculoesquelético/efeitos dos fármacos , Oncostatina M/farmacologia , Osteoartrite/induzido quimicamente , Osteoartrite/patologia , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
5.
Mol Divers ; 8(1): 9-19, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-14964784

RESUMO

Magnetic supports are tested for use in batch affinity capture of proteins. Two types of magnetic polymer composites were used for solid phase synthesis and for the batch affinity chromatography of folate binding protein from a protein mixture. Gly-Gly-L-Methotrexate as well as other analogs were synthesized on magnetic supports consisting of either polyoxyalkyleneamine grafted onto polystyrene beads or a copolymer of polyethylene glycol dimethylacrylamide (PEGA). Both supports incorporated within their matrix sub-micron particles of paramagnetic magnetite. The peptide-methotrexate analogs were attached to the magnetic supports via a photocleavable linker. The bound methotrexate-peptide analogs were equilibrated with a protein mixture consisting of bovine albumin, chicken albumin, folate binding protein, lysozyme, lactoferrin and lactoperoxidase precursor in phosphate buffered saline (PBS) and then after magnetically separating and washing the supports of any unbound components the bound protein was removed either through the photocleavage of the tethered methotrexate-peptide ligand or via exchange with soluble methotrexate. In all cases, the photocleavage or exchange with soluble methotrexate released folate binding protein as the major affinity captured protein. Of the two magnetic supports tested, the PEGA based support was found to be superior to the polyoxyalkyleneamine grafted polystyrene support and comparable to beaded agarose in releasing bound folate binding protein. Of the two methods for removing bound protein, photocleavage of the covalently attached ligand was found to release exclusively folate binding protein as opposed to exchange with soluble methotrexate which released residual amounts of the non-specifically bound proteins bovine and chicken albumin, in addition to folate binding protein. Thus, use of the PEGA based magnetic support in conjunction with a photocleavable linker should help facilitate the automation of multiple parallel affinity chromatography for proteomics applications.


Assuntos
Proteínas de Transporte/isolamento & purificação , Cromatografia de Afinidade/métodos , Ferro/química , Metotrexato/análogos & derivados , Óxidos/química , Proteômica/métodos , Receptores de Superfície Celular/isolamento & purificação , Acrilamidas/química , Ligação Competitiva , Proteínas de Transporte/química , Óxido Ferroso-Férrico , Receptores de Folato com Âncoras de GPI , Magnetismo , Metotrexato/química , Estrutura Molecular , Fotólise , Polietilenoglicóis/química , Poliestirenos/química , Proteínas/química , Proteínas/isolamento & purificação , Receptores de Superfície Celular/química
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