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1.
J Pharmacol Exp Ther ; 356(3): 635-44, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26740668

RESUMO

Prostaglandin (PG) E2 plays a critical role in eliciting inflammation. Nonsteroidal anti-inflammatory drugs and selective inhibitors of cyclooxygenase, which block PGE2 production, have been used as key agents in treating inflammation and pain associated with arthritis and other conditions. However, these agents have significant side effects such as gastrointestinal bleeding and myocardial infarction, since they also block the production of prostanoids that are critical for other normal physiologic functions. Microsomal prostaglandin E2 synthase-1 is a membrane-bound terminal enzyme in the prostanoid pathway, which acts downstream of cyclooxygenase 2 and is responsible for PGE2 production during inflammation. Thus, inhibition of this enzyme would be expected to block PGE2 production without inhibiting other prostanoids and would provide analgesic efficacy without the side effects. In this report, we describe novel microsomal prostaglandin E2 synthase-1 inhibitors that are potent in blocking PGE2 production and are efficacious in a guinea pig monoiodoacetate model of arthralgia. These molecules may be useful in treating the signs and symptoms associated with arthritis.


Assuntos
Analgésicos/química , Analgésicos/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Oxirredutases Intramoleculares/antagonistas & inibidores , Microssomos/efeitos dos fármacos , Fenantrenos/química , Fenantrenos/farmacologia , Analgesia/métodos , Animais , Celecoxib/química , Celecoxib/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Cobaias , Humanos , Oxirredutases Intramoleculares/metabolismo , Masculino , Microssomos/enzimologia , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Prostaglandina-E Sintases , Ratos
2.
Bioorg Med Chem Lett ; 26(14): 3274-3277, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-27261179

RESUMO

A series of triaryl pyrazoles were identified as potent pan antagonists for the retinoic acid receptors (RARs) α, ß and γ. X-ray crystallography and structure-based drug design were used to improve selectivity for RARγ by targeting residue differences in the ligand binding pockets of these receptors. This resulted in the discovery of novel antagonists which maintained RARγ potency but were greater than 500-fold selective versus RARα and RARß. The potent and selective RARγ antagonist LY2955303 demonstrated good pharmacokinetic properties and was efficacious in the MIA model of osteoarthritis-like joint pain. This compound demonstrated an improved margin to RARα-mediated adverse effects.


Assuntos
Desenho de Fármacos , Osteoartrite/tratamento farmacológico , Dor/tratamento farmacológico , Piperazinas/farmacologia , Pirazóis/farmacologia , Receptores do Ácido Retinoico/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade , Receptor gama de Ácido Retinoico
3.
Bioorg Med Chem Lett ; 24(24): 5572-5575, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25466177

RESUMO

Osteoarthritis (OA) and the associated joint pain are highly prevalent and a leading cause of disability. We have previously reported the identification of a series of purines as selective CB2 agonists and the identification of compound 1 as a clinical candidate for the treatment of joint pain. In this article we describe the further SAR development of the purine scaffold leading to the discovery of compound 6 as a potent, CNS penetrating CB2 agonist with high selectivity for CB2 over CB1 and oral efficacy in animal models of chronic OA pain.


Assuntos
Agonistas de Receptores de Canabinoides/uso terapêutico , Dor Crônica/tratamento farmacológico , Piperazinas/química , Purinas/química , Receptor CB2 de Canabinoide/agonistas , Animais , Agonistas de Receptores de Canabinoides/química , Agonistas de Receptores de Canabinoides/farmacocinética , Modelos Animais de Doenças , Cães , Meia-Vida , Humanos , Microssomos Hepáticos/metabolismo , Osteoartrite/tratamento farmacológico , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Purinas/farmacocinética , Purinas/uso terapêutico , Ratos , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-Atividade
4.
JCI Insight ; 8(13)2023 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-37427592

RESUMO

B cells contribute to multiple aspects of autoimmune disorders, and B cell-targeting therapies, including B cell depletion, have been proven to be efficacious in treatment of multiple autoimmune diseases. However, the development of novel therapies targeting B cells with higher efficacy and a nondepleting mechanism of action is highly desirable. Here we describe a nondepleting, high-affinity anti-human CD19 antibody LY3541860 that exhibits potent B cell inhibitory activities. LY3541860 inhibits B cell activation, proliferation, and differentiation of primary human B cells with high potency. LY3541860 also inhibits human B cell activities in vivo in humanized mice. Similarly, our potent anti-mCD19 antibody also demonstrates improved efficacy over CD20 B cell depletion therapy in multiple B cell-dependent autoimmune disease models. Our data indicate that anti-CD19 antibody is a highly potent B cell inhibitor that may have potential to demonstrate improved efficacy over currently available B cell-targeting therapies in treatment of autoimmune conditions without causing B cell depletion.


Assuntos
Doenças Autoimunes , Linfócitos B , Camundongos , Animais , Antígenos CD19 , Doenças Autoimunes/tratamento farmacológico
5.
Bioorg Med Chem Lett ; 22(15): 4962-6, 2012 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-22765893

RESUMO

A focused screening strategy identified thienopyrimidine 1 as a hCB2 cannabinoid receptor agonist with moderate selectivity over the hCB1 receptor. This initial hit suffered from poor in vitro metabolic stability and high in vivo clearance. Structure-activity relationships describe the optimization and modification to a less lipophilic purine core. Examples from this novel series were found to be highly potent and fully efficacious agonists of the human CB2 receptor with excellent selectivity against CB1. Compound 10 possesses good biopharmaceutical properties, is highly water soluble and demonstrates robust oral activity in rodent models of joint pain.


Assuntos
Furanos/química , Purinas/química , Receptor CB2 de Canabinoide/agonistas , Animais , Avaliação Pré-Clínica de Medicamentos , Furanos/farmacocinética , Furanos/uso terapêutico , Meia-Vida , Humanos , Dor/tratamento farmacológico , Purinas/farmacocinética , Purinas/uso terapêutico , Ratos , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-Atividade
6.
Cartilage ; 13(2_suppl): 168S-174S, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34165367

RESUMO

OBJECTIVE: In osteoarthritis, chondrocytes tend to acquire a hypertrophic phenotype, which contributes to the modification of the extracellular matrix, resulting in permanent cartilage changes. In mouse chondrocytes, pro-inflammatory macrophages and pro-inflammatory cytokines have been shown to stimulate hypertrophy via the activation of the nuclear factor kappa B (NF-κB) pathway. Whether or not this also occurs in human chondrocytes remains unclear. We therefore aimed to investigate whether hypertrophy-like responses in human cartilage are driven mainly by intrinsic inflammatory signaling or shaped by specific macrophage populations. DESIGN: Human articular chondrocytes were cultured with pro-inflammatory cytokines or medium conditioned by defined macrophage subsets. Furthermore, the effect of inhibition of NF-κB-dependent gene expression was evaluated using the NF-κB inhibitor SC-514. Hypertrophy was assessed by measuring the transcription level of alkaline phosphatase (ALPL), type X collagen (COL10A1), Indian hedgehog (IHH), and runt-related transcription factor 2 (RUNX2). RESULTS: The expression of hypertrophic genes was not promoted in human chondrocytes by pro-inflammatory cytokines neither pro-inflammatory M(IFNγ + TNFα) macrophages. Inhibition of the NF-κB-dependent gene expression did not affect human articular chondrocyte hypertrophy. However, tissue repair M(IL4) macrophages induced hypertrophy by promoting the expression of COL10A1, RUNX2, and IHH. CONCLUSION: Intrinsic inflammatory signaling activation is not involved in the hypertrophic shift observed in human articular chondrocytes cultured in vitro. However, tissue repair macrophages may contribute to the onset of this detrimental phenotype in human osteoarthritic cartilage, given the effect observed in our experimental models.


Assuntos
Condrócitos , Proteínas Hedgehog , Animais , Condrócitos/metabolismo , Condrogênese , Proteínas Hedgehog/metabolismo , Humanos , Hipertrofia/metabolismo , Macrófagos , Camundongos
7.
J Med Chem ; 64(9): 5470-5484, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33852312

RESUMO

The Th17 pathway has been implicated in autoimmune diseases. The retinoic acid receptor-related orphan receptor C2 (RORγt) is a master regulator of Th17 cells and controls the expression of IL-17A. RORγt is expressed primarily in IL-17A-producing lymphoid cells. Here we describe a virtual screen of the ligand-binding pocket and subsequent screen in a binding assay that identified the 1-benzyl-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-2'-carboxamide scaffold as a starting point for optimization of binding affinity and functional activity guided by structure-based design. Compound 12 demonstrated activity in a mouse PK/PD model and efficacy in an inflammatory arthritis mouse model that were used to define the level and duration of target engagement required for efficacy in vivo. Further optimization to improve ADME and physicochemical properties with guidance from simulations and modeling provided compound 22, which is projected to achieve the level and duration of target engagement required for efficacy in the clinic.


Assuntos
Ligantes , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Tiofenos/química , Animais , Artrite/induzido quimicamente , Artrite/tratamento farmacológico , Artrite/patologia , Sítios de Ligação , Cristalografia por Raios X , Modelos Animais de Doenças , Desenho de Fármacos , Feminino , Meia-Vida , Humanos , Interleucina-17/genética , Interleucina-17/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Camundongos , Simulação de Dinâmica Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/química , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Ligação Proteica , Relação Estrutura-Atividade , Tiofenos/metabolismo , Tiofenos/farmacologia , Tiofenos/uso terapêutico
8.
J Med Chem ; 60(13): 5933-5939, 2017 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-28613895

RESUMO

Aggrecanase-1 and -2 (ADAMTS-4 and ADAMTS-5) are zinc metalloproteases involved in the degradation of aggrecan in cartilage. Inhibitors could provide a means of altering the progression of osteoarthritis. We report the identification of 7 which had good oral pharmacokinetics in rats and showed efficacy in a rat chemical model of osteoarthritis. The projected human dose required to achieve sustained plasma levels ≥10 times the hADAMTS-5 IC50 is 5 mg q.d.


Assuntos
Proteína ADAMTS4/antagonistas & inibidores , Proteína ADAMTS5/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Hidantoínas/química , Hidantoínas/uso terapêutico , Osteoartrite/tratamento farmacológico , Proteína ADAMTS4/metabolismo , Proteína ADAMTS5/metabolismo , Agrecanas/metabolismo , Animais , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/farmacologia , Humanos , Hidantoínas/sangue , Hidantoínas/farmacologia , Masculino , Simulação de Acoplamento Molecular , Osteoartrite/enzimologia , Osteoartrite/metabolismo , Ratos , Ratos Endogâmicos Lew
9.
Pharmacol Res Perspect ; 5(3): e00316, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28603634

RESUMO

Prostaglandin (PG) E2 is the key driver of inflammation associated with arthritic conditions. Inhibitors of PGE 2 production (NSAIDs and Coxibs) are used to treat these conditions, but carry significant side effect risks due to the inhibition of all prostanoids that play important physiological function. The activities of PGE 2 are transduced through various receptor sub-types. Prostaglandin E2 type 4 receptor (EP4) is associated with the development of inflammation and autoimmunity. We therefore are interested in identifying novel EP4 antagonists to treat the signs and symptoms of arthritis without the potential side effects of PGE 2 modulators such as NSAIDs and Coxibs. Novel EP4 antagonists representing distinct chemical scaffolds were identified using a variety of in vitro functional assays and were shown to be selective and potent. The compounds were shown to be efficacious in animal models of analgesia, inflammation, and arthritis.

10.
J Med Chem ; 59(12): 5810-22, 2016 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-27194201

RESUMO

The development of reliable relationships between in vivo target engagement, pharmacodynamic activity, and efficacy in chronic disease models is beneficial for enabling hypothesis-driven drug discovery and facilitating the development of patient-focused candidate selection criteria. Toward those ends, osmotic infusion pumps can be useful for overcoming limitations in the PK properties of proof-of-concept (POC) compounds to accelerate the development of such relationships. In this report, we describe the application of this strategy to the development of hydantoin-derived aggrecanase inhibitors (eg, 3) for the treatment of osteoarthiritis (OA). Potent, selective inhibitors were efficacious in both chemical and surgical models of OA when exposures were sustained in excess of 10 times the plasma IC50. The use of these data for establishing patient-focused candidate selection criteria is exemplified with the characterization of compound 8, which is projected to sustain the desired level of target engagement at a dose of 45 mg qd.


Assuntos
Endopeptidases/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/farmacocinética , Hidantoínas/farmacologia , Hidantoínas/farmacocinética , Osteoartrite/tratamento farmacológico , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Hidantoínas/síntese química , Hidantoínas/química , Masculino , Estrutura Molecular , Osmose/efeitos dos fármacos , Osteoartrite/metabolismo , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade
11.
ACS Med Chem Lett ; 7(9): 857-61, 2016 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-27660691

RESUMO

In an effort to develop a novel therapeutic agent aimed at addressing the unmet need of patients with osteoarthritis pain, we set out to develop an inhibitor for autotaxin with excellent potency and physical properties to allow for the clinical investigation of autotaxin-induced nociceptive and neuropathic pain. An initial hit identification campaign led to an aminopyrimidine series with an autotaxin IC50 of 500 nM. X-ray crystallography enabled the optimization to a lead compound that demonstrated favorable potency (IC50 = 2 nM), PK properties, and a robust PK/PD relationship.

12.
J Med Chem ; 57(24): 10476-85, 2014 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-25415648

RESUMO

A disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and ADAMTS-5 are zinc metalloproteases commonly referred to as aggrecanase-1 and aggrecanase-2, respectively. These enzymes are involved in the degradation of aggrecan, a key component of cartilage. Inhibitors of these enzymes could be potential osteoarthritis (OA) therapies. A series of hydantoin inhibitors of ADAMTS-4 and ADAMTS-5 were identified from a screening campaign and optimized through structure-based drug design to give hydantoin 13. Hydantoin 13 had excellent selectivity over other zinc metalloproteases such as TACE, MMP2, MMP3, MMP13, and MMP14. The compound also produced efficacy in both a chemically induced and surgical model of OA in rats.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Benzofuranos/farmacologia , Hidantoínas/farmacologia , Osteoartrite/tratamento farmacológico , Pró-Colágeno N-Endopeptidase/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Proteína ADAMTS4 , Proteína ADAMTS5 , Animais , Benzofuranos/química , Células Cultivadas , Cristalografia por Raios X , Hidantoínas/química , Masculino , Meniscos Tibiais/efeitos dos fármacos , Meniscos Tibiais/patologia , Microssomos/efeitos dos fármacos , Microssomos/metabolismo , Modelos Anatômicos , Modelos Moleculares , Estrutura Molecular , Osteoartrite/patologia , Inibidores de Proteases/química , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade , Lesões do Menisco Tibial
13.
J Med Chem ; 56(14): 5722-33, 2013 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-23795771

RESUMO

A focused screening strategy identified thienopyrimidine 12 as a cannabinoid receptor type 2 agonist (hCB2) with moderate selectivity over the hCB1 receptor. This initial hit suffered from poor in vitro metabolic stability and high in vivo clearance. Structure-activity relationships describe the optimization and modification to a new more polar series of purine CB2 agonists. Examples from this novel scaffold were found to be highly potent and fully efficacious agonists of the human CB2 receptor with excellent selectivity against CB1, often having no CB1 agonist activity at the highest concentration measured (>100 µM). Compound 26 is a centrally penetrant molecule which possesses good biopharmaceutical properties, is highly water-soluble, and demonstrates robust oral activity in rodent models of joint pain. In addition, the peripherally restricted molecule 22 also demonstrated significant efficacy in the same analgesic model of rodent inflammatory pain.


Assuntos
Osteoartrite/tratamento farmacológico , Purinas/síntese química , Receptor CB2 de Canabinoide/agonistas , Animais , Cães , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Células HEK293 , Humanos , Masculino , Purinas/farmacocinética , Purinas/uso terapêutico , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade
14.
Pain ; 152(5): 975-981, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21185649

RESUMO

The present study examined whether enhancement of endogenous cannabinoid levels by administration of the fatty acid amide hydrolase inhibitor URB597 could modulate joint nociception in 2 rodent models of osteoarthritis (OA). OA-like changes were induced in male Wistar rats by intra-articular injection of monoiodoacetate, while Dunkin-Hartley guinea pigs (age 9-12 months) develop OA naturally and were used as a model of spontaneous OA. Joint nociception was measured by recording electrophysiologically from knee joint primary afferents in response to noxious hyper-rotation of the joint before and after close intra-arterial injection of URB597 (0.03 mg; 0.1 mL bolus); the CB(1) receptor antagonist AM251 (1 mg/kg intraperitoneally) or the CB(2) receptor antagonist AM630 (1 mg/kg intraperitoneally). The effect of systemic URB597 administration (5 mg/kg) on joint pain perception in the monoiodoacetate model was determined by hindlimb incapacitance. Peripheral injection of URB597 caused afferent firing rate to be significantly reduced by up to 56% in the rat OA model and by up to 69% in the guinea pig OA model. Systemic co-administration of AM251, but not AM630, abolished the antinociceptive effect of URB597 in both models. URB597 had no effect in saline-injected control rat joints or in nonarthritic guinea pigs. Systemic URB597 administration significantly reduced hindlimb incapacitance in monoiodoacetate joints and co-administration of the CB(1) antagonist abolished this effect. Local injection of URB597 into OA knee joints reduces mechanonociception and pain, and this response is mediated by CB(1) receptors. Targeting endocannabinoid-metabolizing enzymes in the peripheral nervous system could offer novel therapeutic approaches for the treatment of OA pain.


Assuntos
Artralgia/tratamento farmacológico , Artralgia/etiologia , Benzamidas/uso terapêutico , Carbamatos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Ácido Iodoacético/efeitos adversos , Osteoartrite , Potenciais de Ação/efeitos dos fármacos , Vias Aferentes/citologia , Vias Aferentes/efeitos dos fármacos , Fatores Etários , Animais , Diclofenaco/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Cobaias , Indóis/uso terapêutico , Masculino , Nociceptores/efeitos dos fármacos , Osteoartrite/induzido quimicamente , Osteoartrite/complicações , Osteoartrite/tratamento farmacológico , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Wistar , Fatores de Tempo , Suporte de Carga
15.
Arthritis Rheum ; 48(12): 3452-63, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14673996

RESUMO

OBJECTIVE: To investigate the development of osteoarthritis (OA) after transection of the medial collateral ligament and partial medial meniscectomy in mice in which genes encoding either interleukin-1beta (IL-1beta), IL-1beta-converting enzyme (ICE), stromelysin 1, or inducible nitric oxide synthase (iNOS) were deleted. METHODS: Sectioning of the medial collateral ligament and partial medial meniscectomy were performed on right knee joints of wild-type and knockout mice. Left joints served as unoperated controls. Serial histologic sections were obtained from throughout the whole joint of both knees 4 days or 1, 2, 3, or 4 weeks after surgery. Sections were graded for OA lesions on a scale of 0-6 and were assessed for breakdown of tibial cartilage matrix proteoglycan (aggrecan) and type II collagen by matrix metalloproteinases (MMPs) and aggrecanases with immunohistochemistry studies using anti-VDIPEN, anti-NITEGE, and Col2-3/4C(short) neoepitope antibodies. Proteoglycan depletion was assessed by Alcian blue staining and chondrocyte cell death, with the TUNEL technique. RESULTS: All knockout mice showed accelerated development of OA lesions in the medial tibial cartilage after surgery, compared with wild-type mice. ICE-, iNOS-, and particularly IL-1beta-knockout mice developed OA lesions in the lateral cartilage of unoperated limbs. Development of focal histopathologic lesions was accompanied by increased levels of MMP-, aggrecanase-, and collagenase-generated cleavage neoepitopes in areas around lesions, while nonlesional areas showed no change in immunostaining. Extensive cell death was also detected by TUNEL staining in focal areas around lesions. CONCLUSION: We postulate that deletion of each of these genes, which encode molecules capable of producing degenerative changes in cartilage, leads to changes in the homeostatic controls regulating the balance between anabolism and catabolism, favoring accelerated cartilage degeneration. These observations suggest that these genes may play important regulatory roles in maintaining normal homeostasis in articular cartilage matrix turnover.


Assuntos
Caspase 1/genética , Proteínas da Matriz Extracelular , Interleucina-1/genética , Metaloproteinase 3 da Matriz/genética , Óxido Nítrico Sintase/genética , Osteoartrite do Joelho/fisiopatologia , Osteoartrite do Joelho/cirurgia , Proteínas ADAM , Proteína ADAMTS4 , Proteína ADAMTS5 , Agrecanas , Azul Alciano , Animais , Anticorpos , Colágeno Tipo II/imunologia , Colágeno Tipo II/metabolismo , Corantes , Fragmentação do DNA , Deleção de Genes , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Lectinas Tipo C , Masculino , Ligamento Colateral Médio do Joelho/cirurgia , Meniscos Tibiais/cirurgia , Metaloendopeptidases/imunologia , Metaloendopeptidases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase Tipo II , Oligopeptídeos , Osteoartrite do Joelho/patologia , Fragmentos de Peptídeos , Complicações Pós-Operatórias/patologia , Pró-Colágeno N-Endopeptidase , Proteoglicanas/metabolismo , Coloração e Rotulagem
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