2. Academic Validation
  3. Discovery of SCH 900271, a Potent Nicotinic Acid Receptor Agonist for the Treatment of Dyslipidemia

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

Affiliation

  • 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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