RESUMO
Spleen tyrosine kinase (SYK) is a critical regulator of signaling in a variety of immune cell types such as B-cells, monocytes, and macrophages. Accordingly, there have been numerous efforts to identify compounds that selectively inhibit SYK as a means to treat autoimmune and inflammatory diseases. We previously disclosed GS-9973 (entospletinib) as a selective SYK inhibitor that is under clinical evaluation in hematological malignancies. However, a BID dosing regimen and drug interaction with proton pump inhibitors (PPI) prevented development of entospletinib in inflammatory diseases. Herein, we report the discovery of a second-generation SYK inhibitor, GS-9876 (lanraplenib), which has human pharmacokinetic properties suitable for once-daily administration and is devoid of any interactions with PPI. Lanraplenib is currently under clinical evaluation in multiple autoimmune indications.
RESUMO
Aberrant signaling of phosphoinositide 3-kinase δ (PI3Kδ) has been implicated in numerous pathologies including hematological malignancies and rheumatoid arthritis. Described in this manuscript are the discovery, optimization, and in vivo evaluation of a novel series of pyridine-containing PI3Kδ inhibitors. This work led to the discovery of 35, a highly selective inhibitor of PI3Kδ which displays an excellent pharmacokinetic profile and is efficacious in a rodent model of rheumatoid arthritis.
RESUMO
Inhibition of phosphoinositide 3-kinase δ (PI3Kδ) is an appealing target for several hematological malignancies and inflammatory diseases. Herein, we describe the discovery and optimization of a series of propeller shaped PI3Kδ inhibitors comprising a novel triaminopyrimidine hinge binder. Combinations of electronic and structural strategies were employed to mitigate aldehyde oxidase mediated metabolism. This medicinal chemistry effort culminated in the identification of 52, a potent and highly selective inhibitor of PI3Kδ that demonstrates efficacy in a rat model of arthritis.
Assuntos
Artrite Experimental/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Quinazolinonas/farmacologia , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/enzimologia , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/enzimologia , Células Cultivadas , Colágeno/toxicidade , Cristalografia por Raios X , Modelos Animais de Doenças , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Quinazolinonas/química , Quinazolinonas/farmacocinética , Ratos , Ratos Endogâmicos Lew , Distribuição TecidualRESUMO
Experiments on rat liver slices demonstrated the differential hepatobiliary toxic potency of two anticancer agents, geldanamycin (GEL) and 17-allylaminogeldanamycin (17-AAG), over a 5-day period. This report describes the pattern of toxicity of these agents in dog liver tissue, using the in vitro liver slice culture model. Liver slices (200 microm thick) from male beagle dogs were cultured for 5 days in chemically defined culture medium containing a range of GEL and 17-AAG concentrations (0.1-5 microM). Tissues were evaluated using a panel of clinically relevant biomarkers and histological endpoints. GEL-induced reduction of alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) slice levels, indicators of biliary epithelial cell (BEC) viability, was supported by histological findings showing an increasing loss of BEC as higher concentrations were applied. At the highest concentrations studied, GEL caused both hepatocellular necrosis and BEC loss. Biomarker pattern results in the medium concurred with those from slice biochemistry measurements and histology. 17-AAG, a less potent compound in vivo, elicited more biomarker retention at higher concentrations than did GEL. Histological analysis revealed higher BEC viability and significant retention of BEC proliferation as compared with GEL. However, at the highest concentration, the toxic insult caused a marked decrease in BEC viability and proliferation. Comparison of responses with both compounds indicated that slices exposed to the same concentrations were more sensitive to GEL than to 17-AAG. Dog liver slices can thus be used to evaluate species-, compound-, and concentration-dependent differences in toxicity.
Assuntos
Antibióticos Antineoplásicos/toxicidade , Sistema Biliar/patologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fígado/patologia , Quinonas/toxicidade , Rifabutina/análogos & derivados , Animais , Antimetabólitos , Benzoquinonas , Sistema Biliar/enzimologia , Biomarcadores , Bromodesoxiuridina , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Cães , Imuno-Histoquímica , Técnicas In Vitro , Lactamas Macrocíclicas , Fígado/enzimologia , Testes de Função Hepática , Rifabutina/toxicidadeRESUMO
BACKGROUND: Peer counselling is reported to increase breastfeeding rates. We evaluated an intervention consisting of mainly telephone contact peer counselling programme on breastfeeding duration and exclusivity. METHODS: Peer counsellors (PCs) were mothers who had successfully breastfed and had received formal training. Following a postnatal visit, they provided scheduled telephone consultations (Days 1, 4, 7, Weeks 2, 4, 8, and Month 4) to PC group mothers (n = 100) who continued breastfeeding their infants after discharge. Control group mothers (n = 100) received routine care. RESULTS: After adjusting for mothers' previous breastfeeding experiences, mothers' working status and breastfeeding problems, no statistical differences in mothers' feeding methods (exclusive, almost exclusive or predominant breastfeeding) were noted at the three follow-up times for intervention and control mothers respectively (Day 5: 37%/38%, 46%/53%, 57%/63%; Month 3: 10%/9%, 17%/23%, 20%/26%; Month 6: 2%/1%, 18%/18%, 18%/19%). All differences between the groups were not significant. Also, there was no evidence to suggest that PC intervention prolonged breastfeeding duration. CONCLUSION: The lack of effect of our PC intervention may reflect the low baseline breastfeeding rate and low value placed on breastfeeding in our population, the type of PC intervention or group allocation biases. TRIAL REGISTRATION: ISRCTN93605280.