Document Report Card

ID: ALA2034879

Journal: ACS Med Chem Lett

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

Authors: Palani A, Rao AU, Chen X, Huang X, Su J, Tang H, Huang Y, Qin J, Xiao D, Degrado S, Sofolarides M, Zhu X, Liu Z, McKittrick B, Zhou W, Aslanian R, Greenlee WJ, Senior M, Cheewatrakoolpong B, Zhang H, Farley C, Cook J, Kurowski S, Li Q, van Heek M, Wang G, Hsieh Y, Li F, Greenfeder S, Chintala M.

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.

CiteXplore: 24900372

DOI: 10.1021/ml200243g