Synthesis and SAR of 5-aryl-furan-2-carboxamide derivatives as potent urotensin-II receptor antagonists

Bioorg Med Chem Lett. 2019 Feb 15;29(4):577-580. doi: 10.1016/j.bmcl.2018.12.058. Epub 2018 Dec 29.

Abstract

The synthesis and biological evaluation as potential urotensin-II receptor antagonists of a series of 5-arylfuran-2-carboxamide derivatives 1, bearing a 4-(3-chloro-4-(piperidin-4-yloxy)benzyl)piperazin-1-yl group, are described. The results of a systematic SAR investigation of furan-2-carboxamides with C-5 aryl groups possessing a variety of aryl ring substituents led to identification of the 3,4-difluorophenyl analog 1y as a highly potent UT antagonist with an IC50 value of 6 nM. In addition, this substance was found to display high metabolic stability, and low hERG inhibition and cytotoxicity, and to have an acceptable PK profile.

Keywords: 5-Aryl-furan-2-carboxamide; Antagonists; Cardiovascular disease; Urotensin-II receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Area Under Curve
  • Cell Line
  • Furans / chemical synthesis*
  • Furans / chemistry
  • Furans / pharmacokinetics
  • Furans / pharmacology*
  • Inhibitory Concentration 50
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Furans
  • Receptors, G-Protein-Coupled
  • UTS2R protein, human