| Literature DB >> 24900372 |
Anandan Palani1, Ashwin U Rao1, Xiao Chen1, Xianhai Huang1, Jing Su1, Haiqun Tang1, Ying Huang1, Jun Qin1, Dong Xiao1, Sylvia Degrado1, Michael Sofolarides1, Xiaohong Zhu1, Zhidan Liu1, Brian McKittrick1, Wei Zhou1, Robert Aslanian1, William J Greenlee1, Mary Senior1, Boonlert Cheewatrakoolpong1, Hongtao Zhang1, Constance Farley1, John Cook1, Stan Kurowski1, Qiu Li1, Margaret van Heek1, Gangfeng Wang1, Yunsheng Hsieh1, Fangbiao Li1, Scott Greenfeder1, Madhu Chintala1.
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.Entities:
Keywords: CAD; FFA; HDL-C; LDL-C; Nicotinic acid receptor (NAR) agonist; TG; VLDL-C; dyslipidemia; flushing
Year: 2011 PMID： 24900372 PMCID： PMC4025820 DOI： 10.1021/ml200243g
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345