Discovery of phenylpropanoic acid derivatives containing polar functionalities as potent and orally bioavailable G protein-coupled receptor 40 agonists for the treatment of type 2 diabetes

J Med Chem. 2012 Apr 26;55(8):3756-76. doi: 10.1021/jm2016123. Epub 2012 Apr 11.

Abstract

As part of a program to identify potent GPR40 agonists with drug-like properties suitable for clinical development, the incorporation of polar substituents was explored with the intention of decreasing the lipophilicity of our recently disclosed phenylpropanoic acid derivative 1. This incorporation would allow us to mitigate the cytotoxicity issues observed with compound 1 and enable us to move away from the multifunctional free fatty acid-like structure. Substitutions on the 2',6'-dimethylbiphenyl ring were initially undertaken, which revealed the feasibility of introducing polar functionalities at the biphenyl 4'-position. Further optimization of this position and the linker led to the discovery of several 4'-alkoxybiphenyl derivatives, which showed potent GPR40 agonist activities with the best balance in terms of improved cytotoxicity profiles and favorable pharmacokinetic properties. Among them, 3-{2-fluoro-4-[({4'-[(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2',6'-dimethylbiphenyl-3-yl}methyl)amino]phenyl}propanoic acid (35) exhibited a robust plasma glucose-lowering effect and insulinotropic action during an oral glucose tolerance test in rats with impaired glucose tolerance.

MeSH terms

  • Animals
  • CHO Cells
  • Calcium / metabolism
  • Caspases / metabolism
  • Cell Survival
  • Cricetinae
  • Cyclic S-Oxides / chemical synthesis*
  • Cyclic S-Oxides / pharmacokinetics
  • Cyclic S-Oxides / therapeutic use
  • Diabetes Mellitus, Type 2 / drug therapy
  • Female
  • Glucose Intolerance / drug therapy
  • Hep G2 Cells
  • Humans
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / pharmacokinetics
  • Hypoglycemic Agents / therapeutic use
  • Inhibitory Concentration 50
  • Male
  • Phenylpropionates / chemical synthesis*
  • Phenylpropionates / pharmacokinetics
  • Phenylpropionates / therapeutic use
  • Rats
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism
  • Structure-Activity Relationship

Substances

  • 3-(2-fluoro-4-(((4'-((4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2',6'-dimethylbiphenyl-3-yl)methyl)amino)phenyl)propanoic acid
  • Cyclic S-Oxides
  • FFAR1 protein, human
  • G-protein-coupled receptor 40, rat
  • Hypoglycemic Agents
  • Phenylpropionates
  • Receptors, G-Protein-Coupled
  • Caspases
  • Calcium