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1.
Bioorg Med Chem Lett ; 29(3): 441-448, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30595446

RESUMO

Exploring various cyclization strategies, using a submicromolar pyrazole HTS screening hit 6 as a starting point, a novel indazole based CCR1 antagonist core was discovered. This report presents the design and SAR of CCR1 indazole and azaindazole antagonists leading to the identification of three development compounds, including 19e that was advanced to early clinical trials.


Assuntos
Compostos Aza/farmacologia , Indazóis/farmacologia , Receptores CCR1/antagonistas & inibidores , Compostos Aza/síntese química , Compostos Aza/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Indazóis/síntese química , Indazóis/química , Estrutura Molecular , Receptores CCR1/metabolismo , Relação Estrutura-Atividade
2.
J Pharmacol Exp Ther ; 357(3): 554-61, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27048659

RESUMO

BI 1002494 [(R)-4-{(R)-1-[7-(3,4,5-trimethoxy-phenyl)-[1,6]napthyridin-5-yloxy]-ethyl}pyrrolidin-2-one] is a novel, potent, and selective spleen tyrosine kinase (SYK) inhibitor with sustained plasma exposure after oral administration in rats, which qualifies this molecule as a good in vitro and in vivo tool compound. BI 1002494 exhibits higher potency in inhibiting high-affinity IgE receptor-mediated mast cell and basophil degranulation (IC50 = 115 nM) compared with B-cell receptor-mediated activation of B cells (IC50 = 810 nM). This may be explained by lower kinase potency when the physiologic ligand B-cell linker was used, suggesting that SYK inhibitors may exhibit differential potency depending on the cell type and the respective signal transduction ligand. A 3-fold decrease in potency was observed in rat basophils (IC50 = 323 nM) compared with human basophils, but a similar species potency shift was not observed in B cells. The lower potency in rat basophils was confirmed in both ex vivo inhibition of bronchoconstriction in precision-cut rat lung slices and in reversal of anaphylaxis-driven airway resistance in rats. The different cellular potencies translated into different in vivo efficacy; full efficacy in a rat ovalbumin model (that contains an element of mast cell dependence) was achieved with a trough plasma concentration of 340 nM, whereas full efficacy in a rat collagen-induced arthritis model (that contains an element of B-cell dependence) was achieved with a trough plasma concentration of 1400 nM. Taken together, these data provide a platform from which different estimates of human efficacious exposures can be made according to the relevant cell type for the indication intended to be treated.


Assuntos
Linfócitos B/efeitos dos fármacos , Linfócitos B/enzimologia , Basófilos/efeitos dos fármacos , Basófilos/enzimologia , Naftiridinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirrolidinas/farmacologia , Pirrolidinonas/farmacologia , Quinase Syk/antagonistas & inibidores , Administração Oral , Animais , Humanos , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/enzimologia , Naftiridinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirrolidinas/administração & dosagem , Pirrolidinonas/administração & dosagem , Ratos
3.
PLoS One ; 9(8): e105883, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25170619

RESUMO

Inflammation is associated with immune cells infiltrating into the inflammatory site and pain. CC chemokine receptor 1 (CCR1) mediates trafficking of leukocytes to sites of inflammation. However, the contribution of CCR1 to pain is incompletely understood. Here we report an unexpected discovery that CCR1-mediated trafficking of neutrophils and CCR1 activity on non-hematopoietic cells both modulate pain. Using a genetic approach (CCR1-/- animals) and pharmacological inhibition of CCR1 with selective inhibitors, we show significant reductions in pain responses using the acetic acid-induced writhing and complete Freund's adjuvant-induced mechanical hyperalgesia models. Reductions in writhing correlated with reduced trafficking of myeloid cells into the peritoneal cavity. We show that CCR1 is highly expressed on circulating neutrophils and their depletion decreases acetic acid-induced writhing. However, administration of neutrophils into the peritoneal cavity did not enhance acetic acid-induced writhing in wild-type (WT) or CCR1-/- mice. Additionally, selective knockout of CCR1 in either the hematopoietic or non-hematopoietic compartments also reduced writhing. Together these data suggest that CCR1 functions to significantly modulate pain by controlling neutrophil trafficking to the inflammatory site and having an unexpected role on non-hematopoietic cells. As inflammatory diseases are often accompanied with infiltrating immune cells at the inflammatory site and pain, CCR1 antagonism may provide a dual benefit by restricting leukocyte trafficking and reducing pain.


Assuntos
Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Dor/imunologia , Receptores CCR1/imunologia , Ácido Acético , Animais , Artrite Experimental/genética , Artrite Experimental/imunologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Transplante de Medula Óssea/métodos , Movimento Celular/genética , Movimento Celular/imunologia , Citometria de Fluxo , Adjuvante de Freund , Hiperalgesia/induzido quimicamente , Hiperalgesia/genética , Hiperalgesia/imunologia , Leucócitos/imunologia , Leucócitos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/imunologia , Células Mieloides/metabolismo , Infiltração de Neutrófilos/genética , Neutrófilos/metabolismo , Dor/induzido quimicamente , Dor/genética , Medição da Dor/métodos , Peritonite/genética , Peritonite/imunologia , Peritonite/metabolismo , Receptores CCR1/antagonistas & inibidores , Receptores CCR1/genética
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