Discovery of a biaryl cyclohexene carboxylic acid (MK-6892): a potent and selective high affinity niacin receptor full agonist with reduced flushing profiles in animals as a preclinical candidate

J Med Chem. 2010 Mar 25;53(6):2666-70. doi: 10.1021/jm100022r.

Abstract

Biaryl cyclohexene carboxylic acids were discovered as full and potent niacin receptor (GPR109A) agonists. Compound 1e (MK-6892) displayed excellent receptor activity, good PK across species, remarkably clean off-target profiles, good ancillary pharmacology, and superior therapeutic window over niacin regarding the FFA reduction versus vasodilation in rats and dogs.

MeSH terms

  • Animals
  • Area Under Curve
  • Binding, Competitive
  • CHO Cells
  • Carboxylic Acids / chemistry
  • Carboxylic Acids / pharmacokinetics
  • Carboxylic Acids / pharmacology*
  • Cricetinae
  • Cricetulus
  • Cyclohexanecarboxylic Acids / chemistry
  • Cyclohexanecarboxylic Acids / pharmacokinetics
  • Cyclohexanecarboxylic Acids / pharmacology*
  • Cyclohexenes / chemistry*
  • Dogs
  • Drug Discovery*
  • Drug Evaluation, Preclinical
  • Fatty Acids, Nonesterified / blood
  • Humans
  • Metabolic Clearance Rate
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Chemical
  • Molecular Structure
  • Oxadiazoles / chemistry
  • Oxadiazoles / pharmacokinetics
  • Oxadiazoles / pharmacology*
  • Rats
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Nicotinic / genetics
  • Receptors, Nicotinic / metabolism
  • Structure-Activity Relationship
  • Vasodilation / drug effects

Substances

  • Carboxylic Acids
  • Cyclohexanecarboxylic Acids
  • Cyclohexenes
  • Fatty Acids, Nonesterified
  • HCAR2 protein, human
  • MK 6892
  • Oxadiazoles
  • Receptors, G-Protein-Coupled
  • Receptors, Nicotinic
  • cyclohexene