It appears that a significant LDL cholesterol reduction is associated with a near complete inhibition of CETP, and in this regard, evacetrapib represents a significant advantage over dalcetrapib. elevation was observed in rats dosed with evacetrapib at high exposure multiples compared with Marimastat the positive control, torcetrapib. In addition, in a human being adrenal cortical carcinoma cell collection (H295R cells), evacetrapib did not induce aldosterone or cortisol biosynthesis whereas torcetrapib dramatically induced aldosterone and cortisol biosynthesis. Our data show that evacetrapib is definitely a potent and selective CETP inhibitor without torcetrapib-like off-target liabilities. Evacetrapib is currently in phase II medical development. 0.05 compared with vehicle control. B: HDL cholesterol elevation resulting from the related CETP inhibition. * 0.05 compared with vehicle control. To ensure the observation from the initial single dose in vivo effectiveness study and also to define the relative in vivo potency and efficacy compared with torcetrapib, evacetrapib was further evaluated in the human being CETP/ApoAI double transgenic mice at multiple doses. The ED50 ideals of CETP inhibitory activity 8 h post oral Marimastat dosing for evacetrapib in two dose-response studies were calculated to be 3.5 and 4.1 mg/kg respectively (representative study shown in Fig. 3A) compared with ED50 ideals of 4.0, 2.3 and 1.3 mg/kg of torcetrapib in three independent studies (data not demonstrated). Dose dependent HDL-C elevation was observed for evacetrapib (Figs. 3B), and this was further verified by FPLC analysis of lipoproteins (Fig. 3C). These data indicated that evacetrapib is definitely Marimastat a potent CETP inhibitor in vivo that results in significant HDL-cholesterol elevation in an appropriate animal model. Open in a separate windows Fig. 3. In vivo CETP inhibitory activity of evacetrapib: dose response and ED50 evaluation. A: Dose-dependent inhibition of CETP activity in human being ApoAI and CETP double transgenic mice. Thirty mg/kg torcetrapib was used like a control. B: Related HDL cholesterol elevation resulting from CETP inhibition. * 0.05 compared with vehicle control. C: HDL cholesterol elevation as evaluated by FPLC analysis. Evacetrapib does not increase blood pressure in Zucker Marimastat diabetic fatty rats In the ILLUMINATE trial, 60 mg of torcetrapib daily improved systolic blood pressure by 5.4 mmHg (27). This observation is definitely believed to be an off-target effect of torcetrapib, as dalcetrapib and anacetrapib did not increase blood pressure Cav1.2 in humans. It was therefore essential for us to investigate whether evacetrapib would increase blood pressure in the preclinical stage. To do this, we in the beginning screened several male rat strains (including wild-type Sprague-Dawley rats, ZDF rats, Dahl salt sensitive rats, fructose fed rats and Zucker fatty rats) in which 60 mg/kg of torcetrapib was dosed daily orally for 6 days and the blood pressure was measured hourly in the rats via telemetry on day time 6 during the study. ZDF rats appeared to have the most significant increase in blood pressure resulting from torcetrapib treatment (data not demonstrated), and thus the blood pressure elevation effect of torcetrapib was further evaluated in a dose response study in which 20, 60 and 200 mg/kg doses were used in ZDF rats. As demonstrated in Fig. 4A, torcetrapib dose-dependently improved blood pressure in ZDF rats having a maximum increase in MAP of 14 mmHg in the 1st 2 h post oral dosing. The effect of evacetrapib within the MAP was then evaluated with vehicle, torcetrapib, or evacetrapib with this model. Torcetrapib significantly elevated MAP (7.6 mmHg) at 60 mg/kg whereas evacetrapib did not demonstrate any significant switch in MAP (Fig. 4B). Torcetrapib accomplished a 64-collapse exposure multiple and evacetrapib experienced a 142-collapse exposure multiple. These results suggest that evacetrapib is definitely a potent CETP inhibitor that will not likely induce blood pressure raises in humans. Open in a separate windows Fig. 4. Evacetrapib does not induce blood pressure elevation in ZDF rats. Compound dosing and blood pressure measurement were performed as explained in Methods. A: Dose-dependent induction of blood pressure by torcetrapib in ZDF rats. B: Lack of blood pressure induction in ZDF rats by evacetrapib. Torcetrapib was used like a control in the same study. * 0.05 compared with vehicle control. Evacetrapib does not induce aldosterone or cortisol synthesis in H295R cells Besides the.