3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (MK-0354): a partial agonist of the nicotinic acid receptor, G-protein coupled receptor 109a, with antilipolytic but no vasodilatory activity in mice

J Med Chem. 2008 Aug 28;51(16):5101-8. doi: 10.1021/jm800258p. Epub 2008 Jul 30.


The discovery and profiling of 3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (5a, MK-0354), a partial agonist of GPR109a, is described. Compound 5a retained the plasma free fatty acid lowering effects in mice associated with GPR109a agonism, but did not induce vasodilation at the maximum feasible dose. Moreover, preadministration of 5a blocked the flushing effect induced by nicotinic acid but not that induced by PGD2. This profile made 5a a suitable candidate for further study for the treatment of dyslipidemia.

MeSH terms

  • Adipocytes / drug effects
  • Animals
  • Fatty Acids, Nonesterified / blood
  • Humans
  • Hypolipidemic Agents / chemical synthesis
  • Hypolipidemic Agents / pharmacology*
  • Hypolipidemic Agents / therapeutic use
  • Lipolysis / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pyrazoles / chemical synthesis
  • Pyrazoles / pharmacokinetics*
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, Nicotinic
  • Tetrazoles / chemical synthesis
  • Tetrazoles / pharmacokinetics*
  • Vasodilation / drug effects


  • 3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydrocyclopentapyrazole
  • Fatty Acids, Nonesterified
  • HCAR2 protein, human
  • HCAR3 protein, human
  • Hypolipidemic Agents
  • Pyrazoles
  • Receptors, G-Protein-Coupled
  • Receptors, Nicotinic
  • Tetrazoles