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.

Jun Qin ¹, Ashwin Rao ¹, Xiao Chen ¹, Xiaohong Zhu ¹, Zhidan Liu ¹, Xianhai Huang ¹, Sylvia Degrado ¹, Ying Huang ¹, Dong Xiao ¹, Robert Aslanian ¹, Boonlert Cheewatrakoolpong ², Hongtao Zhang ², Scott Greenfeder ², Constance Farley ², John Cook ², Stan Kurowski ², Qiu Li ², Margaret van Heek ², Madhu Chintala ², Ganfeng Wang ³, Yunsheng Hsieh ³, Fangbiao Li ³, Anandan Palani ¹

Affiliations

1 Department of Medicinal Chemistry.
2 Department of Biology.
3 Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.

PMID: 24900295 DOI: 10.1021/ml100251u

Abstract

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.

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