Discovery of SCH 900271, a Potent Nicotinic Acid Receptor Agonist for the Treatment of Dyslipidemia

Structure-guided optimization of a series of C-5 alkyl substituents led to the discovery of a potent nicotinic acid receptor agonist SCH 900271 (<b>33</b>) with an EC₅₀ of 2 nM in the hu-GPR109a assay. Compound <b>33</b> demonstrated good oral bioavailability in all species. Compound <b>33</b> 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 <b>33</b> 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 <b>33</b> was evaluated in human clinical trials