Discovery of novel pyrimidine and malonamide derivatives as TGR5 agonists

Bioorg Med Chem Lett. 2014 Sep 1;24(17):4271-5. doi: 10.1016/j.bmcl.2014.07.026. Epub 2014 Jul 18.

Abstract

Takeda G-protein-coupled receptor 5 (TGR5) is a promising molecular target for metabolic diseases. A series of 4-(2,5-dichlorophenoxy)pyrimidine and cyclopropylmalonamide derivatives were synthesized as potent agonists of TGR5 based on a bioisosteric replacement strategy. Several compounds exhibited improved potency, compared to a reference compound with a pyridine scaffold. The pharmacokinetic profile of the representative compound 18 was considered moderate.

Keywords: Agonist; Bioisostere; Malonamide; Pyrimidine; TGR5.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Availability
  • Cytochrome P-450 Enzyme Inhibitors / administration & dosage
  • Cytochrome P-450 Enzyme Inhibitors / chemistry
  • Cytochrome P-450 Enzyme Inhibitors / pharmacology*
  • Cytochrome P-450 Enzyme System / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • HEK293 Cells
  • Humans
  • Malonates / administration & dosage
  • Malonates / chemistry
  • Malonates / pharmacology*
  • Mice
  • Mice, Inbred ICR
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Pyrimidines / administration & dosage
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Receptors, G-Protein-Coupled / agonists*
  • Structure-Activity Relationship

Substances

  • Cytochrome P-450 Enzyme Inhibitors
  • GPBAR1 protein, human
  • Malonates
  • Pyrimidines
  • Receptors, G-Protein-Coupled
  • Cytochrome P-450 Enzyme System
  • pyrimidine
  • malonamide