Discovery of a potent nicotinic Acid receptor agonist for the treatment of dyslipidemia

ACS Med Chem Lett. 2010 Dec 8;2(2):171-6. doi: 10.1021/ml100251u. eCollection 2011 Feb 10.


Nicotinic acid has been used clinically for decades to control serum lipoproteins. Nicotinic acid lowers very low-density lipoprotein (VLDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, and lipoprotein-a (LPa), and it is also effective in raising high-density lipoprotein (HDL)-cholesterol. However, nicotinic acid has several side effects in clinical use. The most notable is intense cutaneous vasodilation "flushing" on the upper body and face. We discovered a pyranopyrimidinedione series to be nicotinic acid receptor agonists. A potent nicotinic acid receptor agonist from this series {5-(3-cyclopropylpropyl)-2-(difluoromethyl)-3H-pyrano[2,3-d]pyrimidine-4,7-dione}with reduced flushing side effect in dogs was identified.

Keywords: HDL; Nicotinic acid; VLDL; agonist; dyslipidemia; flushing.