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: 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
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 3 Issue 1 Pg. 63-8 (Jan 12 2012) ISSN: 1948-5875 [Print] United States
• PMID: 24900372 (Publication Type: Journal Article)