In order to elucidate the reasons of high efficacy of
In order to elucidate the reasons of high efficacy of , we evaluated the BOC group itself and the linkage between the BOC group and the benzene ring of A-part. Urea moiety (), the replacement of an oxygen Dacinostat of the BOC group to a nitrogen atom, decreased the activity (EC = 0.12 μM), while the simple alkyl linkage (), the replacement of ether linkage, retained strong activity (EC = 0.047 μM). In addition, the replacement of the terminal -butyl moiety of to the ethyl one () worsened the activity (EC = 0.23 μM). These results implied that both the oxygen atom and the -butyl moiety of the BOC group play important roles. At this time, we do not know the clear reasons, but somehow large lipophilic group, such as the BOC moiety, at the appropriate position may be fitted in the unclear target pocket. Although the BOC compound possessed the potent GLUT4 translocation activity, the liver microsomal stability in mouse was found to be very poor reflecting its high lipophilicity, represented by logD.
Beside the linear groups, cyclic substituents were found to be acceptable, such as hetero aryl methyl moieties ( and ). In addition, aliphatic compound dioxanyl methyl moiety (), derived from the cyclization of compound , gave better result (EC=0.076 μM) compared to (EC=0.23 μM) probably due to the enthalpy decrease by fixing the conformation. Among these compounds, we selected compound for evaluation of the mice model, considering the total profiles, such as activities and pharmacokinetic profiles.
For evaluation, we monitored the blood glucose level after oral dosing of compound , using the severe diabetic mice model (10-week aged mice), which exhibited a high basal plasma glucose level (over 500 mg/ml). As a result, compound showed a significant glucose lowering effect and the efficacy was dose-dependent manner (). It is notable that the blood glucose level ameliorated to a steady level after only about one hour after dosing at 10 mg/kg. PK parameters for this study are shown in . Compound showed a dose-related increase in blood concentration (C and AUC), which clearly lead to the PD results.
We have reported the synthesis and SAR of novel GLUT4 translocation enhancers. Through phenotype screening based on the potency of GLUT4 translocation activity, we found pyridazine derivative as an active lead compound. After further derivatization on each of the parts of , we achieved an improvement in the activity of by as much as several hundred times. Especially, compound bearing both potent activity and good pharmacokinetic profile presented remarkable glucose lowering effects for the severe diabetic mice model (T2DM model), implying that the our novel pyridazine compounds have promising potentials to be used for the treatment of T2DM. Continuous studies including the mechanism of action of these pyridazine compounds will be reported in due course.
Introduction The transparency of the lens is a direct result of its specialized cellular structure and function that combine to minimize light scattering (Donaldson et al., 2017). Structurally the lens is unique in that it grows throughout the lifetime of the individual due to the addition of new cells at the surface and the gradual internalization of older fiber cells into the center or nucleus of the lens. The fiber cells in the lens nucleus represent primary fiber cells, which were laid down early on in eye development and contain lens proteins which are required to last the lifetime of an individual (Robinson, 2006). Secondary fiber cells are derived from epithelial cells, located at the lens equator and are continually added as outer layers after birth (Robinson, 2006). As these fiber cells differentiate, they lose their nuclei, mitochondria and endoplasmic reticulum (Vrensen et al., 1991). Consequently, mature fiber cells of the inner cortex and core utilize anaerobic metabolism, exhibit a reduced metabolic activity and are not able to synthesize new proteins or turnover existing proteins.