Discovery of SCH 900271, a Potent Nicotinic Acid Receptor Agonist for the Treatment of Dyslipidemia.
ACS medicinal chemistry letters(2012)
摘要
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.
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关键词
cad,ffa,hdl-c,ldl-c,nicotinic acid receptor (nar) agonist,tg,vldl-c,dyslipidemia,flushing,biomedical research,bioinformatics
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