Discovery of SCH 900271,
a Potent Nicotinic Acid Receptor
Agonist for the Treatment of Dyslipidemia
- Publication date
- Publisher
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 (<b>33</b>) with an EC<sub>50</sub> 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