Synthesis and evaluation of (E)-2-(5-phenylpent-2-en-4-ynamido)cyclohex-1-ene-1-carboxylate derivatives as HCA2 receptor agonists

Bioorg Med Chem. 2017 Aug 15;25(16):4314-4329. doi: 10.1016/j.bmc.2017.06.028. Epub 2017 Jun 21.

Abstract

Novel series of compounds consisting of 2-amidocyclohex-1-ene carboxylate and phenyl parts which are connected by enyne (compounds 2a-f), but-1-yne (compounds 4a-j), and phenylethylene (compounds 5a-f) linkers as HCA2 full agonists were designed and their functional activity using cAMP assay and binding affinity using radioligand (3H-niacin) binding assay were evaluated. In general, compounds of all three series exhibit similar HCA2 binding and activation profile. However, the activity is strongly dependent on the substituent at the aromatic part of the structure. Among the structures evaluated, the highest affinity and potency in all series were exhibited by compounds containing 4-hydroxy and/or 2-chloro or 2-fluoro substituents. The most active compounds in the enyne and but-1-yne series in the cAMP assay are 2-fluoro,4-hydroxy and 2-chloro,4-hydroxy phenyl derivatives 2f, 4f, and 4g showing potency similar to the previously described 4-hydroxy-biphenyl analogue 5c.

Keywords: 2-Amidocyclohex-1-ene carboxylate; Agonist; CAMP; HCA2; Niacin receptor; Radioligand binding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyclohexenes / chemical synthesis
  • Cyclohexenes / chemistry
  • Cyclohexenes / pharmacology*
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Humans
  • Molecular Structure
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, Nicotinic
  • Structure-Activity Relationship

Substances

  • (E)-2-(5-phenylpent-2-en-4-ynamido)cyclohex-1-ene-1-carboxylate
  • Cyclohexenes
  • HCAR2 protein, human
  • Receptors, G-Protein-Coupled
  • Receptors, Nicotinic