title: Discovery of a potent nicotinic Acid receptor agonist for the treatment of dyslipidemia.
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.
authors.affiliation: Department of Medicinal Chemistry.
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.affiliation: Department of Medicinal Chemistry.
authors.forename: Ashwin
authors.initials: A
authors.lastname: Rao
authors.affiliation: Department of Medicinal Chemistry.
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Medicinal Chemistry.
authors.forename: Zhidan
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry.
authors.forename: Xianhai
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Medicinal Chemistry.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Degrado
authors.affiliation: Department of Medicinal Chemistry.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Medicinal Chemistry.
authors.forename: Dong
authors.initials: D
authors.lastname: Xiao
authors.affiliation: Department of Medicinal Chemistry.
authors.forename: Robert
authors.initials: R
authors.lastname: Aslanian
authors.affiliation: Department of Biology.
authors.forename: Boonlert
authors.initials: B
authors.lastname: Cheewatrakoolpong
authors.affiliation: Department of Biology.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Biology.
authors.forename: Scott
authors.initials: S
authors.lastname: Greenfeder
authors.affiliation: Department of Biology.
authors.forename: Constance
authors.initials: C
authors.lastname: Farley
authors.affiliation: Department of Biology.
authors.forename: John
authors.initials: J
authors.lastname: Cook
authors.affiliation: Department of Biology.
authors.forename: Stan
authors.initials: S
authors.lastname: Kurowski
authors.affiliation: Department of Biology.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Biology.
authors.forename: Margaret
authors.initials: M
authors.lastname: van Heek
authors.affiliation: Department of Biology.
authors.forename: Madhu
authors.initials: M
authors.lastname: Chintala
authors.affiliation: Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Ganfeng
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Yunsheng
authors.initials: Y
authors.lastname: Hsieh
authors.affiliation: Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Fangbiao
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry.
authors.forename: Anandan
authors.initials: A
authors.lastname: Palani
keywords: HDL; Nicotinic acid; VLDL; agonist; dyslipidemia; flushing