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  • Biotin-azide The pharmacodynamic potential of compound was i

    2020-07-31

    The pharmacodynamic potential of Biotin-azide 52 was initially evaluated in an oral triglyceride tolerance test. C57BL/6 mice were treated with vehicle, 0.1, 0.3 or 1mg/kg of 52 30min prior to dosing with a corn oil bolus. Plasma triglyceride (TG) levels were monitored every hour over the course of the 4h test period. Compound 52 inhibited the increase in plasma TG levels in a dose dependent manner, with complete suppression of TG excursion at a dose of 0.3mg/kg (Fig. 2). These results compared favorably with what is seen for the lead clinical candidate 1, which exhibits a comparable potency in this assay. Compound 52 was advanced to a chronic efficacy study in db/db mice maintained on a high fat diet. Animals were dosed with 0.5% methylcellulose vehicle, compound 52 (1, 3 or 15mg/kg, po, Q.D.) or 1 (0.3mg/kg) for 14days. Over the course of the study body weight and food intake were measured daily for each animal (n=8/dose). Plasma endpoints, TG and non-esterified fatty acids (NEFA) were measured on days 0, 7 and 14. On day 14, liver tissue levels of TG and glycogen were evaluated. Separate satellite groups (n=4/dose) was utilized for drug exposure measurements. Over the course of the 14day treatment, compound 52 produced a dose–responsive reduction in body weight (Fig. 3). This effect on body weight was sustained throughout the course of the study, with no rebound in weight gain observed. While there is an initial relative reduction in food intake (FI) relative to controls in the first few days of the study, FI rebounded at the mid-point in the study to then parallel the vehicle treatment group. This suggests that the weight loss observed in these animals was not driven entirely by the reduction in FI. The magnitude of weight loss at 1mg/kg of 52 is approximately equivalent to that observed for 1 at a comparable dose (0.3mg/kg). Free drug plasma exposures generated in satellite animals are plotted in Figure 4 (murine plasmafu=0.09 and 0.35 for 52 and 1, respectively). At the highest dose of 52, plasma free drug exposures were greater than the hDGAT-1 IC50 (murine data not generated) over the duration of the study. At lower doses, exposures were maintained at or near the IC50 for several hours during the course of a 24h period. The disconnect between IC50 coverage and observed efficacy for the lowest dose of 52 and 1, could be the result of difference in species pharmacology or efficacy being driven in part by DGAT-1 inhibition in the liver/intestine, where drug concentrations are likely elevated relative to plasma. Postprandial plasma triglycerides were significantly reduced relative to vehicle control at days 7 and 14 for all doses of 52 and 1 (Fig. 5). There was no dose response to this effect since plasma TG levels were essentially restored to basal levels at all doses of 52. As expected with treatment with a high-fat diet the control mice had increased levels of plasma free fatty acids (FFA) over the course of the study. With DGAT-1 being responsible for not only synthesis, but also hydrolysis of TG, it was not clear what impact inhibiting this enzyme would have on FFA in this study. While no significant changes in plasma FFA levels for the treatment groups were observed on day 7, by the end of the study levels were substantially reduced at all doses of DGAT-1 inhibitor treatment relative to the control animals. Similar effects were also observed for liver TG levels after 14days of treatment with 52. This reduction in liver TG content is consistent with what is observed in DGAT1−/− mice. In high fat fed rodent models an inverse relationship between increased liver TG and reduced glycogen levels has been described as a hallmark of the insulin resistant state. In the current study, day 14 liver glycogen levels were increased relative to control animals in a dose–responsive manner (Fig. 5). This profile of increased liver glycogen and reduced TG levels observed for 52 is consistent with DGAT-1 inhibition leading to an improvement in insulin resistance.