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1.
Top Curr Chem (Cham) ; 377(5): 28, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31563994

RESUMO

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that primarily affects the joints, with the main clinical manifestations being chronic, symmetrical, and peripheral multi-joint inflammatory lesions. Drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (GCs), disease-modifying anti-rheumatic drugs (DMARDs), and biologics play a very important role in the treatment of RA. Of these, the most commonly used are chemical drugs, such as NSAIDs, GCs, and DMARDs. In recent years, a number of new compounds have emerged for the treatment of RA, such as SYK inhibitors, JAK inhibitors, NSAID-CAI drugs, and Syk/PDGFR-α/c-Kit inhibitors. In this review, we summarize the most recently developed anti-RA chemical drugs and discuss the synthesis and biological activities of these various new compounds.


Assuntos
Antirreumáticos/síntese química , Antirreumáticos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Animais , Antirreumáticos/química , Antirreumáticos/uso terapêutico , Humanos , Estrutura Molecular
2.
Sci Rep ; 8(1): 14664, 2018 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-30279454

RESUMO

In oriental medicine, centipede Scolopendra subspinipes mutilans has long been used as a remedy for rheumatoid arthritis (RA), a well-known chronic autoimmune disorder. However, the molecular identities of its bioactive components have not yet been extensively investigated. We sought to identify bioactive molecules that control RA with a centipede. A novel antimicrobial peptide (AMP) (scolopendrasin IX) was identified from Scolopendra subspinipes mutilans. Scolopendrasin IX markedly activated mouse neutrophils, by enhancing cytosolic calcium increase, chemotactic cellular migration, and generation of superoxide anion in neutrophils. As a target receptor for scolopendrasin IX, formyl peptide receptor (FPR)2 mediates neutrophil activation induced by the AMP. Furthermore, scolopendrasin IX administration strongly blocked the clinical phenotype of RA in an autoantibody-injected model. Mechanistically, the novel AMP inhibited inflammatory cytokine synthesis from the joints and neutrophil recruitment into the joint area. Collectively, we suggest that scolopendrasin IX is a novel potential therapeutic agent for the control of RA via FPR2.


Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Antirreumáticos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Proteínas de Insetos/farmacologia , Receptores de Formil Peptídeo/metabolismo , Animais , Peptídeos Catiônicos Antimicrobianos/síntese química , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Antirreumáticos/síntese química , Antirreumáticos/uso terapêutico , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Artrópodes , Autoanticorpos/administração & dosagem , Autoanticorpos/sangue , Células Cultivadas , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Injeções Subcutâneas , Proteínas de Insetos/síntese química , Proteínas de Insetos/uso terapêutico , Masculino , Camundongos , Camundongos Transgênicos , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Cultura Primária de Células , Receptores de Formil Peptídeo/imunologia , Resultado do Tratamento
3.
J Med Chem ; 61(8): 3503-3515, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29605999

RESUMO

A series of novel hydrogen peroxide sensitive prodrugs of methotrexate (MTX) and aminopterin (AMT) were synthesized and evaluated for therapeutic efficacy in mice with collagen induced arthritis (CIA) as a model of chronic rheumatoid arthritis (RA). The prodrug strategy selected is based on ROS-labile 4-methylphenylboronic acid promoieties linked to the drugs via a carbamate linkage or a direct C-N bond. Activation under pathophysiological concentrations of H2O2 proved to be effective, and prodrug candidates were selected in agreement with relevant in vitro physicochemical and pharmacokinetic assays. Selected candidates showed moderate to good solubility, high chemical and enzymatic stability, and therapeutic efficacy comparable to the parent drugs in the CIA model. Importantly, the prodrugs displayed the expected safer toxicity profile and increased therapeutic window compared to MTX and AMT while maintaining a comparable therapeutic efficacy, which is highly encouraging for future use in RA patients.


Assuntos
Aminopterina/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Peróxido de Hidrogênio/química , Metotrexato/análogos & derivados , Metotrexato/uso terapêutico , Pró-Fármacos/uso terapêutico , Aminopterina/síntese química , Aminopterina/farmacocinética , Aminopterina/toxicidade , Animais , Antirreumáticos/síntese química , Antirreumáticos/farmacocinética , Antirreumáticos/toxicidade , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/metabolismo , Ácidos Borônicos/síntese química , Ácidos Borônicos/farmacocinética , Ácidos Borônicos/uso terapêutico , Ácidos Borônicos/toxicidade , Colágeno Tipo II/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Células MCF-7 , Masculino , Metotrexato/farmacocinética , Metotrexato/toxicidade , Camundongos Endogâmicos DBA , Microssomos Hepáticos/metabolismo , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Pró-Fármacos/toxicidade , Solubilidade
4.
J Med Chem ; 61(8): 3454-3477, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29589441

RESUMO

Epigenetic modifiers of the histone deacetylase (HDAC) family contribute to autoimmunity, cancer, HIV infection, inflammation, and neurodegeneration. Hence, histone deacetylase inhibitors (HDACi), which alter protein acetylation, gene expression patterns, and cell fate decisions, represent promising new drugs for the therapy of these diseases. Whereas pan-HDACi inhibit all 11 Zn2+-dependent histone deacetylases (HDACs) and cause a broad spectrum of side effects, specific inhibitors of histone deacetylase 6 (HDAC6i) are supposed to have less side effects. We present the synthesis and biological evaluation of Marbostats, novel HDAC6i that contain the hydroxamic acid moiety linked to tetrahydro-ß-carboline derivatives. Our lead compound Marbostat-100 is a more potent and more selective HDAC6i than previously established well-characterized compounds in vitro as well as in cells. Moreover, Marbostat-100 is well tolerated by mice and effective against collagen type II induced arthritis. Thus, Marbostat-100 represents a most selective known HDAC6i and the possibility for clinical evaluation of a HDAC isoform-specific drug.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Benzamidas/uso terapêutico , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/uso terapêutico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/toxicidade , Antirreumáticos/síntese química , Antirreumáticos/farmacologia , Antirreumáticos/toxicidade , Artrite Experimental/induzido quimicamente , Artrite Reumatoide/induzido quimicamente , Benzamidas/líquido cefalorraquidiano , Benzamidas/farmacologia , Benzamidas/toxicidade , Sítios de Ligação , Carbolinas/síntese química , Carbolinas/farmacologia , Carbolinas/uso terapêutico , Carbolinas/toxicidade , Linhagem Celular Tumoral , Colágeno Tipo II , Células HEK293 , Desacetilase 6 de Histona/química , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/toxicidade , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Ácidos Hidroxâmicos/toxicidade , Masculino , Camundongos Endogâmicos DBA , Simulação de Acoplamento Molecular , Peixe-Zebra
5.
Future Med Chem ; 9(17): 1995-2009, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28789563

RESUMO

AIM: 16 thioxoquinazolines were evaluated in vivo for anti-inflammatory activity using carrageenan-induced paw edema assay. RESULTS: In particular, out of the targets (1-16), compounds 4 and 6 displayed the highest anti-inflammatory activity (≥80%) and furtherly tested against complete Freund's adjuvant-induced arthritic rats. Significant reduction in the serum level of IL-1ß, COX-2 and prostaglandin E2 in the complete Freund's adjuvant rats is demonstrated by compounds 4 and 6. Furthermore, compound 4 showed non-selective activity against COX-1 and COX 2, however, compound 6 was specific toward COX-2. Molecular docking study has demonstrated the possible binding modes of the active quinazolines 4 and 6 in the COX-2 active site. CONCLUSION: These targets could be used as templates for further development of new derivatives with potent anti-inflammatory activity.


Assuntos
Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Inibidores de Ciclo-Oxigenase/farmacologia , Edema/tratamento farmacológico , Quinazolinas/farmacologia , Animais , Antirreumáticos/síntese química , Antirreumáticos/química , Carragenina , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Ratos , Relação Estrutura-Atividade
6.
Future Med Chem ; 9(11): 1193-1211, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28722479

RESUMO

AIM: Autoimmune disorders have complex pathophysiology and focus is laid on the development of multitargeted agents. Two well-established kinases: SYK and JAK3, were considered to design dual inhibitors as potential therapeutics using various molecular-modeling approaches. Mehodology: Pharmacophore models for SYK and JAK3 were generated using oxindole-based inhibitors. Furthermore, an in-house database was designed that was screened against the best selected models. The obtained hits were employed for docking analysis and subjected to MM-GBSA analysis and molecular dynamic simulation. RESULTS: Top five oxindole derivatives were synthesized and evaluated for in vitro SYK and JAK3 activity. The most active compound 4a was evaluated for in vivo antiarthritic activity. It showed significant anti-arthritic activity. CONCLUSION: Thus, the designed inhibitors resulted in potential therapeutic agents for rheumatoid arthritis.


Assuntos
Antirreumáticos/síntese química , Artrite Experimental/tratamento farmacológico , Indóis/síntese química , Janus Quinase 3/antagonistas & inibidores , Quinase Syk/antagonistas & inibidores , Animais , Antirreumáticos/farmacologia , Desenho de Drogas , Feminino , Indóis/farmacologia , Masculino , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Oxindois , Relação Quantitativa Estrutura-Atividade , Ratos Wistar , Estereoisomerismo
7.
J Med Chem ; 59(17): 7915-35, 2016 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-27531604

RESUMO

Bruton's tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous autoimmune diseases. This article will detail the structure-activity relationships (SARs) leading to a novel second generation series of potent and selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide 6 (BMS-935177) was selected to advance into clinical development.


Assuntos
Antirreumáticos/química , Carbazóis/química , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinazolinonas/química , Administração Oral , Tirosina Quinase da Agamaglobulinemia , Animais , Antirreumáticos/síntese química , Antirreumáticos/farmacocinética , Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Disponibilidade Biológica , Carbazóis/síntese química , Carbazóis/farmacocinética , Carbazóis/farmacologia , Linhagem Celular , Cristalografia por Raios X , Cães , Humanos , Macaca fascicularis , Camundongos , Microssomos Hepáticos/metabolismo , Permeabilidade , Proteínas Tirosina Quinases/química , Quinazolinonas/síntese química , Quinazolinonas/farmacocinética , Quinazolinonas/farmacologia , Relação Estrutura-Atividade
8.
MAbs ; 7(5): 805-11, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26230301

RESUMO

Humira® (adalimumab) is a recombinant human IgG1 monoclonal antibody (mAb) glycoprotein consisting of 1330 amino acids that is specific for human tumor necrosis factor (TNF). The biological activity and clinical profile of mAb therapeutics, including adalimumab, is influenced by their protein structure and glycosylation patterns, which can be affected by the expression system, cell culture conditions and purification process methodology. While clinical outcome cannot yet be attributed to many of the individual structural features that constitute a mAb, it is evident that detailed structural attribute analysis is necessary if structural contributions to function are to be comprehensively defined. Adalimumab product quality data generated from over a decade of manufacturing across multiple production sites and through a series of manufacturing scale changes are presented here. These data reveal a consistent and tightly controlled profile for the product.


Assuntos
Adalimumab/química , Anti-Inflamatórios/química , Antirreumáticos/química , Medicamentos sob Prescrição/normas , Controle de Qualidade , Anti-Inflamatórios/síntese química , Afinidade de Anticorpos , Antirreumáticos/síntese química , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Ensaio de Imunoadsorção Enzimática , Humanos
9.
Arch Pharm (Weinheim) ; 348(7): 463-74, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26032727

RESUMO

Four scaffolds of varied benzylidene derivatives were synthesized and evaluated as Syk inhibitors for the treatment of rheumatoid arthritis (RA). Among these 31 compounds, 3-benzylidene pyrrolidine-2,5-dione derivatives (including 12k) universally showed good Syk inhibitory activities in the low micromolar to submicromolar range. In the cellular profiling, compound 12k, the most efficient compound, showed excellent antiproliferative activity against fibroblast-like synoviocytes (FLS)-RA, and demonstrated potencies for suppression of IL-6 and MMP-3 secretion almost equal to R406 (positive control). The oral efficacy of 12k in the murine collagen-induced arthritis model was significant, despite being weaker than R406. Taken together, all preliminary pharmacological results supported 12k as a potential small-molecule inhibitor targeting Syk for the treatment of RA.


Assuntos
Antirreumáticos/síntese química , Compostos de Benzilideno/síntese química , Inibidores Enzimáticos/síntese química , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Antirreumáticos/química , Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/enzimologia , Artrite Experimental/imunologia , Compostos de Benzilideno/química , Compostos de Benzilideno/farmacologia , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/imunologia , Humanos , Interleucina-6/metabolismo , Masculino , Metaloproteinase 3 da Matriz/metabolismo , Camundongos Endogâmicos DBA , Estrutura Molecular , Relação Estrutura-Atividade , Quinase Syk , Membrana Sinovial/citologia , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/imunologia
10.
Bioorg Med Chem ; 23(13): 3059-80, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-26014481

RESUMO

Osteoarthritis and rheumatoid arthritis are the two most common types of arthritis. Cartilage breakdown is a key feature of both diseases which contributes to the pain and joint deformity experienced by patients. Therefore, anti-arthritis drugs are of great importance. The aim of this review is to present recent progress in studies of various agents against osteoarthritis and rheumatoid arthritis. The structures and activities of anti-arthritic agents, which used in medical practice or are in development, are presented and discussed. The effects and mechanisms of action of opioids, glucocorticoids, non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, natural products derived from plants, nutraceuticals, and a number of new and perspective agents are considered. Various perspective targets for the treatment of osteoarthritis and rheumatoid arthritis are also discussed. Trials of good quality are needed to draw solid conclusions regarding efficacy of many of the studied agents. Unfortunately, to date, there is no pharmacologic agent proven to prevent the progression of both diseases, and there is an urgent need for further development of better anti-arthritic agents.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Drogas em Investigação/uso terapêutico , Osteoartrite/tratamento farmacológico , Analgésicos Opioides/síntese química , Analgésicos Opioides/uso terapêutico , Anti-Inflamatórios não Esteroides/síntese química , Antirreumáticos/síntese química , Artrite Reumatoide/patologia , Artrite Reumatoide/fisiopatologia , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Cartilagem/efeitos dos fármacos , Cartilagem/patologia , Cartilagem/fisiopatologia , Drogas em Investigação/síntese química , Glucocorticoides/síntese química , Glucocorticoides/uso terapêutico , Humanos , Articulações/efeitos dos fármacos , Articulações/patologia , Articulações/fisiopatologia , Metotrexato/síntese química , Metotrexato/uso terapêutico , Osteoartrite/patologia , Osteoartrite/fisiopatologia , Dor/patologia , Dor/fisiopatologia , Dor/prevenção & controle
11.
J Med Chem ; 56(11): 4764-85, 2013 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-23659214

RESUMO

Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.


Assuntos
Antirreumáticos/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Imidazóis/síntese química , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Piridinas/síntese química , Pirróis/síntese química , Administração Oral , Animais , Antirreumáticos/química , Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/etiologia , Disponibilidade Biológica , Permeabilidade da Membrana Celular , Colágeno , Cristalografia por Raios X , Cães , Haplorrinos , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Imidazóis/química , Imidazóis/farmacologia , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Janus Quinase 1/química , Janus Quinase 2/química , Células Madin Darby de Rim Canino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Piridinas/química , Piridinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Ratos , Estereoisomerismo
12.
Bioorg Med Chem Lett ; 23(10): 3070-4, 2013 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-23562062
13.
Expert Opin Drug Metab Toxicol ; 9(8): 969-81, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23574578

RESUMO

INTRODUCTION: Current treatment strategy for rheumatoid arthritis (RA) focuses on tight disease control and remission. The present understanding of the immune-pathological process of RA, mechanism of synthetic DMARDs and the clinical experience of the drugs have raised certain concerns over their clinical use. AREAS COVERED: The review summarizes latest concepts in the pathogenesis of RA, and the mechanism of action and pharmacokinetics of commonly used synthetic DMARDs. It also covers the principle of enzyme and receptor kinetics, and limitation of current knowledge on RA disease measures. EXPERT OPINION: There is a need to rationalize the use of synthetic DMARDs to help improve RA treatment. One recommendation to assist the rationalization of this treatment is by the construction of suitable models of the disease process, thereby augmenting treatment options. Currently, the dosage and duration of this type of treatment is based on its overall effect and clinical outcome. Each DMARD will confer its effect on a specific component of the multilevel, multicellular, pathological process of RA. Furthermore, developing definitive biomarkers could help to better assess the disease at its various stages instead of using conventional RA measures for drug titration and to help in the rationalization of drug regimen. Integrating pharmacokinetic and pharmacodynamic properties into this model will also help in improving treatment outcomes.


Assuntos
Antirreumáticos/síntese química , Antirreumáticos/farmacocinética , Artrite Reumatoide/tratamento farmacológico , Antirreumáticos/administração & dosagem , Biomarcadores/sangue , Humanos , Modelos Biológicos , Resultado do Tratamento
14.
Ann Rheum Dis ; 72(5): 748-53, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23041841

RESUMO

OBJECTIVES: To identify a new disease-modifying osteoarthritis drug (DMOAD) candidate that can effectively repair cartilage by promoting chondrogenic differentiation and halt osteoarthritis (OA) progression by suppressing aberrant hypertrophy. METHODS: We screened 2500 natural and synthetic small compounds for chondrogenic agents via four steps using the Col2GFP-ATDC5 system and identified a small thienoindazole derivative compound, TD-198946, as a novel DMOAD candidate. We tested its efficacy as a DMOAD via intra-articular injections directly into the joint space in a surgically-induced mouse model of OA both at the onset (prevention model) and 4 weeks after (repair model) OA induction. The downstream molecules were screened by microarray analysis. We further investigated the mechanism of the drug action and its molecular target using in vitro and in vivo assays. RESULTS: TD-198946 strongly induced chondrogenic differentiation without promoting hypertrophy in cell and metatarsal organ cultures. When administered directly into the joint space, TD-198946 successfully prevented and repaired degeneration of the articular cartilage. TD-198946 exerted its effect through the regulation of Runx1 expression, which was downregulated in both mouse and human OA cartilage compared with normal tissue. CONCLUSIONS: Our data suggest that TD-198946 is a novel class of DMOAD candidate, and that targeting Runx1 will provide a promising new approach in the development of disease-modifying drugs against OA.


Assuntos
Antirreumáticos/farmacologia , Condrogênese/efeitos dos fármacos , Subunidade alfa 2 de Fator de Ligação ao Core/antagonistas & inibidores , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Indazóis/farmacologia , Osteoartrite do Joelho/tratamento farmacológico , Osteoartrite do Joelho/prevenção & controle , Animais , Antirreumáticos/síntese química , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Diferenciação Celular/efeitos dos fármacos , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Modelos Animais de Doenças , Desenho de Drogas , Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Indazóis/síntese química , Injeções Intra-Articulares , Articulação do Joelho/efeitos dos fármacos , Articulação do Joelho/patologia , Masculino , Camundongos , Osteoartrite do Joelho/patologia , RNA Mensageiro/metabolismo
15.
Bioorg Med Chem Lett ; 22(6): 2266-70, 2012 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-22342143
16.
J Med Chem ; 55(6): 2623-40, 2012 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-22339472

RESUMO

Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly soluble 14l was selected as the optimal compound. Oral efficacy in the murine collagen-induced arthritis (CIA) model for rheumatoid arthritis (RA) supported 14l as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA. Compound 14l (SB1578) was progressed into development and is currently undergoing phase 1 clinical trials in healthy volunteers.


Assuntos
Antirreumáticos/síntese química , Artrite Reumatoide/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Janus Quinase 2/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Antirreumáticos/farmacocinética , Antirreumáticos/farmacologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Linhagem Celular , Permeabilidade da Membrana Celular , Colágeno Tipo II , Cães , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Janus Quinase 2/fisiologia , Macaca mulatta , Masculino , Camundongos , Camundongos Nus , Microssomos/metabolismo , Modelos Moleculares , Ratos , Transdução de Sinais/efeitos dos fármacos , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , TYK2 Quinase/antagonistas & inibidores
17.
J Med Chem ; 55(2): 709-16, 2012 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-22175799

RESUMO

Osteoarthritis (OA) is a nonsystemic disease for which no oral or parenteral disease-modifying osteoarthritic drug (DMOAD) is currently available. Matrix metalloproteinase 13 (MMP-13) has attracted attention as a target with disease-modifying potential because of its major role in tissue destruction associated with OA. Being localized to one or a few joints, OA is amenable to intra-articular (IA) therapy, which has distinct advantages over oral therapies in terms of increasing therapeutic index, by maximizing drug delivery to cartilage and minimizing systemic exposure. Here we report on the synthesis and biological evaluation of a non-zinc binding MMP-13 selective inhibitor, 4-methyl-1-(S)-({5-[(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)carbamoyl]pyrazolo[1,5-a]pyrimidine-7-carbonyl}amino)indan-5-carboxylic acid (1), that is uniquely suited as a potential IA-DMOAD: it has long durability in the joint, penetrates cartilage effectively, exhibits nearly no detectable systemic exposure, and has remarkable efficacy.


Assuntos
Antirreumáticos/síntese química , Benzoxazinas/síntese química , Indanos/síntese química , Inibidores de Metaloproteinases de Matriz , Osteoartrite/tratamento farmacológico , Animais , Antirreumáticos/farmacocinética , Antirreumáticos/farmacologia , Benzoxazinas/farmacocinética , Benzoxazinas/farmacologia , Cartilagem Articular/metabolismo , Bovinos , Técnicas In Vitro , Indanos/farmacocinética , Indanos/farmacologia , Injeções Intra-Articulares , Masculino , Permeabilidade , Ratos , Ratos Sprague-Dawley , Solubilidade , Estereoisomerismo
18.
Bioorg Med Chem Lett ; 21(12): 3708-11, 2011 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-21565499

RESUMO

High throughput screening (HTS) of our compound file provided an attractive lead compound with modest P2X(7) receptor antagonist potency and high selectivity against a panel of receptors and channels, but also with high human plasma protein binding and a predicted short half-life in humans. Multi-parameter optimization was used to address the potency, physicochemical and pharmacokinetic properties which led to potent P2X(7)R antagonists with good disposition properties. Compound 33 (CE-224,535) was advanced to clinical studies for the treatment of rheumatoid arthritis.


Assuntos
Benzamidas , Descoberta de Drogas , Antagonistas do Receptor Purinérgico P2 , Receptores Purinérgicos P2X7/metabolismo , Uracila/análogos & derivados , Administração Oral , Animais , Antirreumáticos/síntese química , Antirreumáticos/química , Antirreumáticos/farmacocinética , Antirreumáticos/farmacologia , Benzamidas/síntese química , Benzamidas/química , Benzamidas/farmacocinética , Benzamidas/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2/síntese química , Antagonistas do Receptor Purinérgico P2/química , Antagonistas do Receptor Purinérgico P2/farmacocinética , Antagonistas do Receptor Purinérgico P2/farmacologia , Ratos , Relação Estrutura-Atividade , Uracila/síntese química , Uracila/química , Uracila/farmacocinética , Uracila/farmacologia
19.
J Med Chem ; 53(24): 8650-62, 2010 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-21090716

RESUMO

Sphingosine 1-phosphate lyase (S1PL) has been characterized as a novel target for the treatment of autoimmune disorders using genetic and pharmacological methods. Medicinal chemistry efforts targeting S1PL by direct in vivo evaluation of synthetic analogues of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI, 1) led to the discovery of 2 (LX2931) and 4 (LX2932). The immunological phenotypes observed in S1PL deficient mice were recapitulated by oral administration of 2 or 4. Oral dosing of 2 or 4 yielded a dose-dependent decrease in circulating lymphocyte numbers in multiple species and showed a therapeutic effect in rodent models of rheumatoid arthritis (RA). Phase I clinical trials indicated that 2, the first clinically studied inhibitor of S1PL, produced a dose-dependent and reversible reduction of circulating lymphocytes and was well tolerated at dose levels of up to 180 mg daily. Phase II evaluation of 2 in patients with active rheumatoid arthritis is currently underway.


Assuntos
Aldeído Liases/antagonistas & inibidores , Antirreumáticos/síntese química , Imidazóis/síntese química , Isoxazóis/síntese química , Oximas/síntese química , Aldeído Liases/genética , Animais , Antirreumáticos/farmacocinética , Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Artrite Experimental/patologia , Pressão Sanguínea/efeitos dos fármacos , Movimento Celular , Cães , Frequência Cardíaca/efeitos dos fármacos , Imidazóis/farmacocinética , Imidazóis/farmacologia , Isoxazóis/farmacocinética , Isoxazóis/farmacologia , Linfócitos/efeitos dos fármacos , Linfócitos/fisiologia , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Oximas/farmacocinética , Oximas/farmacologia , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade
20.
J Med Chem ; 53(17): 6398-411, 2010 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-20712346

RESUMO

The p38 mitogen-activated protein kinase (MAPK) plays an important role in the production of proinflammatory cytokines, making it an attractive target for the treatment of various inflammatory diseases. A series of pyridazinopyridinone compounds were designed as novel p38 kinase inhibitors. A structure-activity investigation identified several compounds possessing excellent potency in both enzyme and human whole blood assays. Among them, compound 31 exhibited good pharmacokinetic properties and showed excellent selectivity against other related kinases. In addition, 31 demonstrated efficacy in a collagen-induced arthritis disease model in rats.


Assuntos
Antirreumáticos/síntese química , Piridazinas/síntese química , Piridonas/síntese química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Fator 2 Ativador da Transcrição/metabolismo , Animais , Antirreumáticos/farmacocinética , Antirreumáticos/farmacologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Sítios de Ligação , Colágeno , Feminino , Humanos , Interleucina-8/biossíntese , Interleucina-8/sangue , Lipopolissacarídeos/farmacologia , Masculino , Modelos Moleculares , Fosforilação , Piridazinas/farmacocinética , Piridazinas/farmacologia , Piridonas/farmacocinética , Piridonas/farmacologia , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/farmacologia
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