Small structural changes of the imidazopyridine diacylglycerol acyltransferase 2 (DGAT2) inhibitors produce an improved safety profile.

Small molecule DGAT2 inhibitors have shown promise for the treatment of metabolic diseases in preclinical models. Herein, we report the first toxicological evaluation of imidazopyridine-based DGAT2 inhibitors and show that the arteriopathy associated with imidazopyridine 1 can be mitigated with small structural modifications, and is thus not mechanism related.

Effect of endothelin antagonists with or without BQ 788 on ET-1 responses in pithed rats.

The overall effects of endothelin-1 (ET-1) on blood pressure are caused by a composite activation of constrictor ETA and ETB receptors and dilator ETB receptors. Therefore, it is difficult to accurately compare the ETA activity of selective ETA receptor antagonists (BQ 123 and BMS 182874) with mixed ETA/ETB antagonists (SB 209670 and bosentan) on the cumulative dose-response curve to ET-1. The development of a selective ETB antagonist (BQ 788), which inhibits both the dilator and constrictor ETB receptors, offered the opportunity to investigate the role of ETB receptors in the response to exogenous ET-1 in the pithed rat. BQ 788 (3 mg/kg) resulted in an eightfold leftward shift in the ET-1 dose-response curve, suggesting a significant involvement of ETB dilator receptors. In the absence or presence of BQ 788, each ET antagonist evoked a rightward shift from vehicle. With the exception of BMS 182874, BQ 788 increased the magnitude of the shifts. Furthermore, the profile of the shifts changed from nonparallel to parallel in the presence of BQ 788. The inclusion of BQ 788 also altered the rank order of the ET antagonists tested. The results presented describe an in vivo system that accurately characterizes the ETA activity of ET antagonists.

Sarafotoxin S6c elicits a non-ETA or non-ETB-mediated pressor response in the pithed rat.

Sarafotoxin S6c (Sx6c) is reported to evoke depressor and pressor effects via activation of endothelin (ET) ETB receptors located on the endothelium and smooth muscle, respectively. We have examined the effects of the selective ETB receptor antagonist BQ 788 on the fall and rise in diastolic blood pressure induced by Sx6c (1 nmol/kg, i.v.) in pithed rats. A dose-dependent reduction in both depressor and pressor response was observed. BQ 788 completely ablated the Sx6c-mediated fall in blood pressure at 1 mg/kg. In contrast, the pressor response was not completely abolished by 10 mg/kg BQ 788 (10 mg/kg: 16.5 +/- 3.0 mm Hg vs. control 49.0 +/- 2.5 mm Hg). Co-administration of the ETA receptor antagonist BQ 123 (1.5 mg/kg) with BQ 788 produced no further antagonism of the Sx6c-mediated pressor response. BQ 788 plus BQ 123 (1.5 mg/kg) totally blocked the pressor response to ET-1 (0.1 nmol/kg, i.v.) suggesting a difference in the mechanism of action between the two agonists. In conclusion, a portion of the Sx6c-induced pressor response is resistant to blockade by known ETA and ETB receptor antagonists. Whether Sx6c acts on a novel ET receptor or produces a nonspecific effect remains to be determined.