Discovery of SCH 900271, a Potent Nicotinic Acid Receptor Agonist for the Treatment of Dyslipidemia
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- 作者：Anandan Palani ; Ashwin U. Rao ; Xiao Chen ; Xianhai Huang ; Jing Su ; Haiqun Tang ; Ying Huang ; Jun Qin ; Dong Xiao ; Sylvia Degrado ; Michael Sofolarides ; Xiaohong Zhu ; Zhidan Liu ; Brian McKittrick ; Wei Zhou ; Robert Aslanian ; William J. Greenlee ; Mary Senior ; Boonlert Cheewatrakoolpong ; Hongtao Zhang ; Constance Farley ; John Cook ; Stan Kurowski ; Qiu Li ; Margaret van Heek ; Gangfeng Wang ; Yunsheng Hsieh ; Fangbiao Li ; Scott Greenfeder ; Madhu Chintala
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：January 12, 2012
- 年：2012
- 卷：3
- 期：1
- 页码：63-68
- 全文大小：286K
- 年卷期：v.3,no.1(January 12, 2012)
- ISSN：1948-5875
文摘
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.