Discovery of a Potent Nicotinic Acid Receptor Agonist for the Treatment of Dyslipidemia

摘要

Nicotinic acid has been used clinically for decades to control serum lipoproteins. Nicotinic acid lowers very low-density lipoprotein (VLDL)-cholester- ol, 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 pyranopyr- imidinedione 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.