RESUMO
Asthma, chronic obstructive pulmonary disease (COPD) and acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are characterized by neutrophilic inflammation and elevated levels of leukotriene B4 (LTB4). However, the exact role of LTB4 pathways in mediating pulmonary neutrophilia and the potential therapeutic application of LTB4 receptor antagonists in these diseases remains controversial. Here we show that a novel dual BLT1 and BLT2 receptor antagonist, RO5101576, potently inhibited LTB4-evoked calcium mobilization in HL-60 cells and chemotaxis of human neutrophils. RO5101576 significantly attenuated LTB4-evoked pulmonary eosinophilia in guinea pigs. In non-human primates, RO5101576 inhibited allergen and ozone-evoked pulmonary neutrophilia, with comparable efficacy to budesonide (allergic responses). RO5101576 had no effects on LPS-evoked neutrophilia in guinea pigs and cigarette smoke-evoked neutrophilia in mice and rats. In toxicology studies RO5101576 was well-tolerated. Theses studies show differential effects of LTB4 receptor antagonism on neutrophil responses in vivo and suggest RO5101576 may represent a potential new treatment for pulmonary neutrophilia in asthma.
Assuntos
Benzodioxóis/farmacologia , Fenilpropionatos/farmacologia , Pneumonia/tratamento farmacológico , Primatas , Receptores do Leucotrieno B4/antagonistas & inibidores , Animais , Benzodioxóis/uso terapêutico , Benzodioxóis/toxicidade , Cães , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Cobaias , Células HL-60 , Humanos , Hipersensibilidade/complicações , Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , Masculino , Camundongos , Ozônio/farmacologia , Fenilpropionatos/uso terapêutico , Fenilpropionatos/toxicidade , Pneumonia/induzido quimicamente , Pneumonia/complicações , Pneumonia/metabolismo , Ratos , Receptores do Leucotrieno B4/metabolismo , Fumar/efeitos adversos , Testes de ToxicidadeRESUMO
CRTH2 is one of the prostaglandin D2 receptors and plays a proinflammatory role in allergic diseases. Gene expression markers in whole blood induced by CRTH2 activation have not previously been reported. Using microarray analyses of 54 675 genes, we revealed modest gene expression changes in human whole blood stimulated in vitro by a selective CRTH2 agonist, DK-PGD2. Five genes were found to exhibit 1.5- to 2.6-fold changes in expression. The expression of Charcot-Leyden crystal protein/galectin-10 (CLC/Gal-10) in particular was consistently enhanced in human whole blood stimulated by DK-PGD2, as confirmed by quantitative real-time polymerase chain reaction analyses. DK-PGD(2)-induced increases in blood CLC/Gal-10 mRNA levels were largely attenuated by the CRTH2 antagonist CAY10471.Thus, the DK-PGD2-induced CLC/Gal-10 mRNA level can serve as a potential marker for monitoring pharmacodynamic effects of blood exposure to CRTH2 modulating agents.
Assuntos
Biomarcadores/metabolismo , Glicoproteínas/genética , Lisofosfolipase/genética , RNA Mensageiro/genética , Receptores Imunológicos/sangue , Receptores de Prostaglandina/sangue , Sequência de Bases , Primers do DNA , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da PolimeraseRESUMO
The inhibition of LTB(4) binding to and activation of G-protein-coupled receptors BLT1 and BLT2 is the premise of a treatment for several inflammatory diseases. In a lead optimization effort starting with the leukotriene B(4) (LTB(4)) receptor antagonist (2), members of a series of 3,5-diarylphenyl ethers were found to be highly potent inhibitors of LTB(4) binding to BLT1 and BLT2 receptors, with varying levels of selectivity depending on the substitution. In addition, compounds 33 and 38 from this series have good in vitro ADME properties, good oral bioavailability, and efficacy after oral delivery in guinea pig LTB(4) and nonhuman primate allergen challenge models. Further profiling in a rat non-GLP toxicity experiment provided the rationale for differentiation and selection of one compound (33) for clinical development.