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

  • ACS Med Chem Lett. 2011 Nov 24;3(1):63-8. doi: 10.1021/ml200243g.
Anandan Palani  1 ,  Ashwin U Rao  1 ,  Xiao Chen  1 ,  Xianhai Huang  1 ,  Jing Su  1 ,  Haiqun Tang  1 ,  Ying Huang  1 ,  Jun Qin  1 ,  Dong Xiao  1 ,  Sylvia Degrado  1 ,  Michael Sofolarides  1 ,  Xiaohong Zhu  1 ,  Zhidan Liu  1 ,  Brian McKittrick  1 ,  Wei Zhou  1 ,  Robert Aslanian  1 ,  William J Greenlee  1 ,  Mary Senior  1 ,  Boonlert Cheewatrakoolpong  1 ,  Hongtao Zhang  1 ,  Constance Farley  1 ,  John Cook  1 ,  Stan Kurowski  1 ,  Qiu Li  1 ,  Margaret van Heek  1 ,  Gangfeng Wang  1 ,  Yunsheng Hsieh  1 ,  Fangbiao Li  1 ,  Scott Greenfeder  1 ,  Madhu Chintala  1
Affiliations
  • 1. Department of Medicinal Chemistry, Department of Biology, and Department of Drug Metabolism & Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
PMID: 24900372 DOI: 10.1021/ml200243g
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.

Keywords
CAD; FFA; HDL-C; LDL-C; Nicotinic acid receptor (NAR) agonist; TG; VLDL-C; dyslipidemia; flushing.
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