Effects of pyrazole partial agonists on HCA2-mediated flushing and VLDL-triglyceride levels in mice.

BACKGROUND AND PURPOSE Niacin can effectively treat dyslipidaemic disorders. However, its clinical use is limited due to the cutaneous flushing mediated by the nicotinic acid receptor HCA2. In the current study, we evaluated two partial agonists for HCA2, LUF6281 and LUF6283, with respect to their anti-dyslipidaemic potential and cutaneous flushing effect. EXPERIMENTAL APPROACH In vitro potency and efficacy studies with niacin and the two HCA2 partial agonists were performed using HEK293T cells stably expressing human HCA2. Normolipidaemic C57BL/6 mice received either niacin or the HCA2 partial agonists (400 mg·kg−1·day−1) once a day for 4 weeks for evaluation of their effects in vivo. KEY RESULTS Radioligand competitive binding assay showed Ki values for LUF6281 and LUF6283 of 3 and 0.55 µM. [35S]-GTPγS binding revealed the rank order of their potency as niacin > LUF6283 > LUF6281. All three compounds reduced plasma VLDL-triglyceride concentrations similarly, while LUF6281 and LUF6283, in contrast to niacin, did not also exhibit the unwanted flushing side effect in C57BL/6 mice. Niacin reduced the expression of lipolytic genes HSL and ATGL in adipose tissue by 50%, whereas LUF6281 and LUF6283 unexpectedly did not. In contrast, the decrease in VLDL-triglyceride concentration induced by LUF6281 and LUF6283 was associated with a parallel >40% reduced expression of APOB within the liver. CONCLUSIONS AND IMPLICATIONS The current study identifies LUF6281 and LUF6283, two HCA2 partial agonists of the pyrazole class, as promising drug candidates to achieve the beneficial lipid lowering effect of niacin without producing the unwanted flushing side effect. [ABSTRACT FROM AUTHOR]