Discovery of SCH 900271, a potent nicotinic acid receptor agonist for the treatment of dyslipidemia

…, D Xiao, S Degrado, M Sofolarides, X Zhu…

Index: Palani, Anandan; Rao, Ashwin U.; Chen, Xiao; Huang, Xianhai; Su, Jing; Tang, Haiqun; Huang, Ying; Qin, Jun; Xiao, Dong; Degrado, Sylvia; Sofolarides, Michael; Zhu, Xiaohong; Liu, Zhidan; McKittrick, Brian; Zhou, Wei; Aslanian, Robert; Greenlee, William J.; Senior, Mary; Cheewatrakoolpong, Boonlert; Zhang, Hongtao; Farley, Constance; Cook, John; Kurowski, Stan; Li, Qiu; Van Heek, Margaret; Wang, Gangfeng; Hsieh, Yunsheng; Li, Fangbiao; Greenfeder, Scott; Chintala, Madhu ACS Medicinal Chemistry Letters, 2012 , vol. 3, # 1 p. 63 - 68

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Citation Number: 8

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 ...