title: Discovery of SCH 900271, a Potent Nicotinic Acid Receptor Agonist for the Treatment of Dyslipidemia.
abstract: Structure-guided optimization of a series of C-5 alkyl substituents led to the discovery of a potent nicotinic acid receptor agonist SCH 900271 (33) with an EC50 of 2 nM in the hu-GPR109a assay. Compound 33 demonstrated good oral bioavailability in all species. Compound 33 exhibited dose-dependent inhibition of plasma free fatty acid (FFA) with 50% FFA reduction at 1.0 mg/kg in fasted male beagle dogs. Compound 33 had no overt signs of flushing at doses up to 10 mg/kg with an improved therapeutic window to flushing as compared to nicotinic acid. Compound 33 was evaluated in human clinical trials.
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Anandan
authors.initials: A
authors.lastname: Palani
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Ashwin U
authors.initials: AU
authors.lastname: Rao
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Xianhai
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Haiqun
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Dong
authors.initials: D
authors.lastname: Xiao
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Degrado
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Sofolarides
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Zhidan
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: McKittrick
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Aslanian
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Mary
authors.initials: M
authors.lastname: Senior
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Boonlert
authors.initials: B
authors.lastname: Cheewatrakoolpong
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Constance
authors.initials: C
authors.lastname: Farley
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: John
authors.initials: J
authors.lastname: Cook
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Stan
authors.initials: S
authors.lastname: Kurowski
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Margaret
authors.initials: M
authors.lastname: van Heek
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Gangfeng
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and 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 Medicinal Chemistry, Department of Biology, and 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, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Greenfeder
authors.affiliation: Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Madhu
authors.initials: M
authors.lastname: Chintala
keywords: CAD; FFA; HDL-C; LDL-C; Nicotinic acid receptor (NAR) agonist; TG; VLDL-C; dyslipidemia; flushing