RESUMO
Starting from a weak screening hit, potent and selective inhibitors of the MALT1 protease function were elaborated. Advanced compounds displayed high potency in biochemical and cellular assays. Compounds showed activity in a mechanistic Jurkat T cell activation assay as well as in the B-cell lymphoma line OCI-Ly3, which suggests potential use of MALT1 inhibitors in the treatment of autoimmune diseases as well as B-cell lymphomas with a dysregulated NF-κB pathway. Initially, rat pharmacokinetic properties of this compound series were dominated by very high clearance which could be linked to amide cleavage. Using a rat hepatocyte assay a good in vitro-in vivo correlation could be established which led to the identification of compounds with improved PK properties.
Assuntos
Antineoplásicos/farmacologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/antagonistas & inibidores , Piperidinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Hepatócitos/efeitos dos fármacos , Humanos , Células Jurkat , Microssomos/efeitos dos fármacos , Estrutura Molecular , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Piperidinas/síntese química , Piperidinas/química , Proteólise/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
We applied ancient DNA methods to shed light on the origin of ancient Hungarians and their relation to modern populations. Hungarians moved into the Carpathian Basin from the Eurasian Pontic steppes in the year 895 AD as a confederation of seven tribes, but their further origin remains obscure. Here, we present 17 mtDNA haplotypes and four Y-chromosome haplogroups, which portray the genetic composition of an entire small cemetery of the first generation Hungarians. Using novel algorithms to compare these mitochondrial DNA haplogroups with other ancient and modern Eurasian data, we revealed that a significant portion of the Hungarians probably originated from a long ago consolidated gene pool in Central Asia-South Siberia, which still persists in modern Hungarians. Another genetic layer of the early Hungarians was obtained during their westward migrations by admixing with various populations of European origin, and an important component of these was derived from the Caucasus region. Most of the modern populations, which are genetically closest relatives of ancient Hungarians, today speak non-Indo-European languages. Our results contribute to our understanding of the peopling of Europe by providing ancient DNA data from a still genetically poorly studied period of medieval human migrations.
Assuntos
Cromossomos Humanos Y/genética , DNA Mitocondrial/genética , Haplótipos , População Branca/genética , Algoritmos , Arqueologia , Cemitérios , Feminino , Genética Médica/métodos , Genética Populacional , Genoma Humano , Migração Humana , Humanos , Hungria , Masculino , FilogeniaRESUMO
Recent reports have suggested critical roles of myeloid cells in tumor invasion and metastasis, although these findings have not led to therapeutics. Using a mouse model for liver dissemination, we show that mouse and human colon cancer cells secrete CC-chemokine ligands CCL9 and CCL15, respectively, and recruit CD34(+) Gr-1(-) immature myeloid cells (iMCs). They express CCL9/15 receptor CCR1 and produce matrix metalloproteinases MMP2 and MMP9. Lack of the Ccr1, Mmp2, or Mmp9 gene in the host dramatically suppresses outgrowths of disseminated tumors in the liver. Importantly, CCR1 antagonist BL5923 blocks the iMC accumulation and metastatic colonization and significantly prolongs the survival of tumor-bearing mice. These results suggest that CCR1 antagonists can provide antimetastatic therapies for patients with disseminated colon cancer in the liver.
Assuntos
Diferenciação Celular , Neoplasias do Colo/patologia , Neoplasias Hepáticas/secundário , Células Mieloides/patologia , Receptores CCR1/metabolismo , Animais , Quimiocinas CC/metabolismo , Neoplasias do Colo/metabolismo , Modelos Animais de Doenças , Humanos , Ligantes , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Proteínas Inflamatórias de Macrófagos/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Células Mieloides/metabolismo , Receptores CCR1/antagonistas & inibidores , Transdução de Sinais , Análise de SobrevidaRESUMO
Teachers with poor neuroliteracy fail to distinguish scientific evidence from neuromyths (NM), which might lead to the implementation of pseudoscientific educational methods. The prevalence of NM and general knowledge about the brain (GKAB) among in-service and pre-service teachers has been assessed in multiple countries, but no such study has been performed in Hungary. The aims of this study were to (1) assess the neuroliteracy of pre-service teachers, (2) compare the results with those of previous studies and (3) analyze the factors influencing neuroliteracy. Our sample included 822 pre-service teachers from 12 Hungarian universities. We developed a survey including 10 NM and 13 GKAB statements, adapted from a widely used questionnaire. The average rate of incorrect answers to NM was 56.9%, whereas the average rate of correct answers to GKAB was 70.9%. Male gender and frequency of using Facebook as the primary information source about neuroscience were the only predictors of NM acceptance. In comparison with other studies, the Hungarian pre-service teachers had the second highest endorsement of NM. The most prevalent NM were linked to motor functions, which might be related to the widespread use and promotion of motor therapies in Hungary.
RESUMO
Pyrrolo[2,3-f]isoquinoline based amino acids, tetracyclic lactams and cyclic ketone analogues are described as novel MK2 inhibitors with IC(50) as low as 5nM and good selectivity profiles against a number of related kinases including ERK, p38alpha and JNKs. TNFalpha release was suppressed from human peripheral blood mononuclear cells (hPBMCs), and a representative compound inhibited LPS induced TNFalpha release in mice illustrating the potential of this series to provide orally active MK2 inhibitors.
Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/química , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Administração Oral , Aminoácidos/síntese química , Aminoácidos/química , Aminoácidos/farmacologia , Animais , Sítios de Ligação , Cristalografia por Raios X , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Isoquinolinas/química , Cetonas/síntese química , Cetonas/química , Cetonas/farmacologia , Lactamas/síntese química , Lactamas/química , Lactamas/farmacologia , Camundongos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Pirróis/química , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
New, selective 3-aminopyrazole based MK2-inhibitors were discovered by scaffold hopping strategy. The new derivatives proved to inhibit intracellular phosphorylation of hsp27 as well as LPS-induced TNFalpha release in cells. In addition, selected derivative 14e also inhibited LPS-induced TNFalpha release in vivo.
Assuntos
Descoberta de Drogas , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazóis/química , Linhagem Celular Tumoral , Células Cultivadas , Cristalografia por Raios X , Descoberta de Drogas/métodos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Conformação Proteica , Proteínas Serina-Treonina Quinases/metabolismo , Pirazóis/metabolismo , Pirazóis/farmacologiaRESUMO
Spirocyclopropane- and spiroazetidine-substituted tetracycles 13D-E and 16A are described as orally active MK2 inhibitors. The spiroazetidine derivatives are potent MK2 inhibitors with IC(50)<3 nM and inhibit the release of TNFalpha (IC(50)<0.3 microM) from hPBMCs and hsp27 phosphorylation in anisomycin stimulated THP-1 cells. The spirocyclopropane analogues are less potent against MK2 (IC(50)=0.05-0.23 microM), less potent in cells (IC(50)<1.1 microM), but show good oral absorption. Compound 13E (100mg/kg po; bid) showed oral activity in rAIA and mCIA, with significant reduction of swelling and histological score.
Assuntos
Ácido Azetidinocarboxílico/química , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Administração Oral , Animais , Ácido Azetidinocarboxílico/síntese química , Ácido Azetidinocarboxílico/farmacologia , Azetidinas/química , Sítios de Ligação , Linhagem Celular , Cristalografia por Raios X , Ciclopropanos/química , Ciclopropanos/farmacologia , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Compostos de Espiro/química , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Bruton's tyrosine kinase (BTK) is a member of the TEC kinase family and is selectively expressed in a subset of immune cells. It is a key regulator of antigen receptor signaling in B cells and of Fc receptor signaling in mast cells and macrophages. A BTK inhibitor will likely have a positive impact on autoimmune diseases which are caused by autoreactive B cells and immune-complex driven inflammation. We report the design, optimization, and characterization of potent and selective covalent BTK inhibitors. Starting from the selective reversible inhibitor 3 binding to an inactive conformation of BTK, we designed covalent irreversible compounds by attaching an electrophilic warhead to reach Cys481. The first prototype 4 covalently modified BTK and showed an excellent kinase selectivity including several Cys-containing kinases, validating the design concept. In addition, this compound blocked FcγR-mediated hypersensitivity in vivo. Optimization of whole blood potency and metabolic stability resulted in compounds such as 8, which maintained the excellent kinase selectivity and showed improved BTK occupancy in vivo.
RESUMO
Pyrrolo-pyrimidones of the general structure 1 were synthesized and evaluated for their potential as MK2 inhibitors. Potent derivatives were discovered which inhibit MK2 in the nanomolar range and show potent inhibition of cytokine release from LPS-stimulated monocytes. These derivatives were shown to inhibit phosphorylation of hsp27, a downstream target of MK2 and are modestly selective in a panel of 28 kinases.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinonas/síntese química , Pirimidinonas/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Artrite Reumatoide/tratamento farmacológico , Técnicas de Química Combinatória , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Desenho de Fármacos , Proteínas de Choque Térmico HSP27/antagonistas & inibidores , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Estrutura Molecular , Monócitos/efeitos dos fármacos , Fosforilação , Pirimidinonas/química , Pirróis/química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidoresRESUMO
MAP-activated protein kinase 2 (MK2) plays an important role in the regulation of innate immune response as well as in cell survival upon DNA damage. Despite its potential for the treatment of inflammation and cancer, to date no MK2 low molecular weight inhibitors have reached the clinic, mainly due to inadequate absorption, distribution, metabolism, and excretion (ADME) properties. We describe here an approach based on specifically placed fluorine within a recently described pyrrole-based MK2 inhibitor scaffold for manipulation of its physicochemical and ADME properties. While preserving target potency, the novel fluoro-derivatives showed greatly improved permeability as well as enhanced solubility and reduced in vivo clearance leading to significantly increased oral exposure.
RESUMO
PURPOSE: The purpose of this study was to create a physical education (PE) attitude scale and examine how it is associated with aerobic capacity (AC). METHOD: Participants (n = 961, aged 15-20 years) were randomly selected from 26 Hungarian high schools. AC was estimated from performance on the Progressive Aerobic Cardiovascular and Endurance Run test, and the attitude scale had 31 items measured on a Likert scale that ranged from 1 to 5. Principal component analysis was used to examine the structure of the questionnaire while several 2-way analyses of variance and multiple linear regression (MLR) were computed to examine trends in AC and test the association between component scores obtained from the attitude scale and AC, respectively. RESULTS: Five components were identified: health orientation in PE (C1), avoid failure in PE (C2), success orientation in PE (C3), attitude toward physical activity (C4), and cooperation and social experience in PE (C5). There was a statistically significant main effect for sex on C3 (p < .05), C4 (p < .001), and C5 (p < .05) indicating that boys' scores were higher than girls. The Sex × Age interaction was also statistically significant (p < .05) and follow-up comparisons revealed sex differences in C5 for 15-year-old participants. Girls showed statistically significant higher values than boys in C5 at the age of 16 years. MLR results revealed that component scores were significantly associated with AC (p < .05). Statistically significant predictors included C1, C2, C3, and C4 for boys and C2 and C4 for girls. CONCLUSION: The 5-component scale seems to be suitable for measuring students' attitudes toward PE. The design of the study does not allow for direct associations between attitudes and AC but suggests that these 2 might be related.
Assuntos
Atitude , Fenômenos Fisiológicos Cardiovasculares , Educação Física e Treinamento , Aptidão Física , Estudantes/psicologia , Adolescente , Fatores Etários , Feminino , Humanos , Hungria , Masculino , Consumo de Oxigênio , Instituições Acadêmicas , Fatores Sexuais , Inquéritos e Questionários , Adulto JovemRESUMO
We recently described a new model to study non-invasively with magnetic resonance imaging (MRI) the effects of compounds to prevent and/or resolve airway inflammation induced by ovalbumin in the lungs of actively sensitised rats. We report here the effects of 4-(4-fluorophenyl)-2-(1-methylpiperidin-4-yl)-5-(2-(1-(S)-phenylethyl)amino-4-pyridinyl)thiazole fumarate (Compound 1), which exhibits inhibitory activity against p38alpha and p38beta2 and residual activity on c-Jun amino-terminal kinase (JNK)2 mitogen-activated protein (MAP) kinases, on the oedematous signals detected by MRI and generated by antigen challenge in the lungs of sensitized rats. Compound 1 (10 mg kg(-1)) given orally 1 h prior to allergen challenge significantly reduced the oedematous signal measured at 24 h. Similar effects were seen with a synthetic corticosteroid, mometasone furoate (0.3 mg kg(-1)), given intratracheally 3 h prior to challenge. For both compounds, inhibition of the oedematous signal was accompanied by reductions in the inflammatory parameters in the bronchoalveolar lavage fluid measured 24 h after challenge with ovalbumin. Compound 1 (10 mg kg(-1)) administered 24 h after challenge with ovalbumin did not change the rate of resolution of the signal detected by MRI in the lungs. In contrast, mometasone furoate (0.3 mg kg(-1)) significantly increased resolution of these signals, which was evident 3 h after drug administration and maintained to 48 h post challenge. Collectively, our data suggest that the p38 MAP kinase inhibitor Compound 1 shows a different profile than glucocorticosteroids since its ability to resolve existing inflammation is limited.
Assuntos
Inibidores Enzimáticos/uso terapêutico , Imageamento por Ressonância Magnética/métodos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Pneumonia/tratamento farmacológico , Pneumonia/enzimologia , Animais , Inibidores Enzimáticos/farmacologia , Humanos , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Ratos , Ratos Endogâmicos BNRESUMO
Diabetic nephropathy is associated with interstitial macrophage infiltrates, but their contribution to disease progression is unclear. We addressed this question by blockade of chemokine receptor (CCR)1 because CCR1 mediates the macrophage recruitment to the renal interstitium. In fact, when CCR1 was blocked with BL5923, a novel orally available CCR1 antagonist, the interstitial recruitment of ex vivo labeled macrophages was markedly decreased in uninephrectomized male db/db mice with advanced diabetic nephropathy. Likewise, BL5923 (60 mg/kg, twice a day) orally administered from months 5 to 6 of life reduced the numbers of interstitial macrophages in uninephrectomized db/db mice. This was associated with reduced numbers of Ki-67 proliferating tubular epithelial and interstitial cells, tubular atrophy, and interstitial fibrosis in uninephrectomized db/db mice. Glomerular pathology and proteinuria were not affected by the CCR1 antagonist. BL5923 reduced renal mRNA expression of Ccl2, Ccr1, Ccr2, Ccr5, transforming growth factor-beta1, and collagen I-alpha1 when compared with untreated uninephrectomized male db/db mice of the same age. Thus, we identified a previously unrecognized role for interstitial macrophages for tubulointerstitial injury, loss of peritubular microvasculature, interstitial inflammation, and fibrosis in type 2 diabetic db/db mice. These data identify oral treatment with the CCR1 antagonist BL5923 as a potential therapy for late-stage diabetic nephropathy.
Assuntos
Diabetes Mellitus Tipo 2/complicações , Neuropatias Diabéticas/patologia , Rim/efeitos dos fármacos , Macrófagos/patologia , Administração Oral , Animais , Antígenos de Diferenciação/análise , Linhagem Celular , Células Cultivadas , Neuropatias Diabéticas/etiologia , Expressão Gênica/efeitos dos fármacos , Imuno-Histoquímica , Rim/metabolismo , Rim/patologia , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Microscopia de Fluorescência , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CCR1 , Receptores CCR2 , Receptores de Quimiocinas/antagonistas & inibidores , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Crescimento Transformador beta1/genéticaRESUMO
The design, synthesis, and the biological evaluation of 2-benzamido-pyrimidines as novel IKK inhibitors are described. By optimization of the lead compound 3, compounds 16 and 24 are identified as good inhibitors of IKK2 with IC(50) values of 40 and 25 nM, respectively. Compound 16 also demonstrated significant in vivo activity in an acute model of cytokine release.
Assuntos
Química Farmacêutica/métodos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Quinase I-kappa B/antagonistas & inibidores , Pirimidinas/síntese química , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Concentração Inibidora 50 , Modelos Químicos , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
A test library with three novel p38alpha inhibitory scaffolds and a narrow set of substituents was prepared. Appropriate combination of substituent and scaffold generated potent p38alpha inhibitors, for example, pyrazolo[3,4-b]pyridine 9, pyrazolo[3,4-d]pyrimidine 18a and pyrazolo[3,4-b]pyrazine 23b with potent in vivo activity upon oral administration in animal models of rheumatoid arthritis.
Assuntos
Artrite Experimental/tratamento farmacológico , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Pirazinas/administração & dosagem , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Pirimidinas/administração & dosagem , Administração Oral , Animais , Modelos Animais de Doenças , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Pirazinas/síntese química , Pirazinas/química , Pirazóis/síntese química , Pirazóis/química , Piridinas/síntese química , Piridinas/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Cinnamides as novel CCR1 antagonist chemotypes are described with high affinity to human and rodent receptors. A1B1 and A4B7 showed oral activity in the mouse collagen induced arthritis.
Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Experimental/tratamento farmacológico , Receptores de Quimiocinas/antagonistas & inibidores , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Humanos , Camundongos , Ratos , Receptores CCR1 , Relação Estrutura-AtividadeRESUMO
A library of trisubstituted oxazoles, thiazoles, imidazoles (1,2,4- and 2,4,5-substituted) and imidazo[1,2-b]pyridines was prepared and evaluated in vitro as p38alpha inhibitors and in vivo in several models of rheumatoid arthritis. Four structures--32, 37, 45 and 59--were identified as potent inhibitors of p38alpha with high efficacy in the LPS induced TNFalpha release model in the mouse, the adjuvant induced arthritis and the collagen induced arthritis in the rat with ED50s between 1.0 and 9.5 mg/kg p.o.
Assuntos
Antirreumáticos/síntese química , Piridinas/síntese química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Colágeno , Modelos Animais de Doenças , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Imidazóis/química , Lipopolissacarídeos/farmacologia , Camundongos , Oxazóis/química , Piridinas/farmacologia , Piridinas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Tiazóis/química , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Benzoylpyridines and benzophenones were synthesized and evaluated in vitro as p38alpha inhibitors and in vivo in several models of rheumatoid arthritis. Oral activity was found to depend upon substitution: 1,1-dimethylpropynylamine substituted benzophenone 10b (IC50: 14 nM) and pyridinoyl substituted benzimidazole 17b (IC50: 21 nM) showed highest efficacy and selectivity with ED50s of 9.5 and 8.6 mg/kg p.o. in CIA.
Assuntos
Benzofenonas/síntese química , Inibidores Enzimáticos/síntese química , Boca/metabolismo , Piridinas/síntese química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Benzofenonas/farmacologia , Benzofenonas/uso terapêutico , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Concentração Inibidora 50 , Piridinas/farmacologia , Piridinas/uso terapêutico , Ratos , Relação Estrutura-AtividadeRESUMO
2,6-Diamino-3,5-difluoropyridinyl substituted pyridinylimidazoles, -pyrroles, -oxazoles, -thiazoles and -triazoles have been identified as novel p38alpha inhibitors. Pyridinylimidazole 11 potently inhibited LPS-induced TNFalpha in mice, showed good efficacy in the established rat adjuvant (ED(50): 10 mg/kg po b.i.d.) and collagen induced arthritis (ED(50): 5 mg/kg po b.i.d.) with disease modifying properties based on histological analysis of the joints.