Estrogen Receptor Modulators: Identification and Structure-Activity Relationships of Potent ERalpha-selective Tetrahydroisoquinoline Ligands

J Med Chem. 2003 Jul 3;46(14):2945-57. doi: 10.1021/jm030086h.

Abstract

As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), tetrahydroisoquinoline derivative 27 was discovered by high throughput screening. Successive replacements of the p-F substituent of 27 by an aminoethoxy side chain and of the 1-H of the tetrahydroisoquinoline core by a 1-Me group provided analogues 19 and 20. These compounds showed potencies in a cell-based reporter gene assay (ERE assay) varying between 0.6 and 20 nM and displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line with IC(50)s in the range of 2-36 nM. The effect of N-phenyl substituents on the activity and pharmacokinetic properties of tetrahydroisoquinoline analogues was explored. As a result of this investigation, two potent derivatives bearing a p-F N-aryl group, 19c and 20c, were discovered as candidates suitable for further profiling. To gain insight into the ligand-receptor interaction, the X-ray crystallographic structure of the 1-H tetrahydroisoquinoline derivative (R)-18a in complex with ERalpha-ligand binding domain (LBD)(301)(-)(553)/C-->S triple mutant was solved to 2.28 A. An overlay of this X-ray crystal structure with that reported for the complex of ERalpha-LBD(301)(-)(553)/carboxymethylated C and raloxifene (5) shows that both compounds bind to the same cleft of the receptor and display comparable binding modes, with differences being observed in the conformation of their "D-ring" phenyl groups.

MeSH terms

  • Administration, Oral
  • Animals
  • Binding Sites
  • Biological Availability
  • Cell Division / drug effects
  • Crystallography, X-Ray
  • Estradiol / pharmacology
  • Estrogen Receptor Modulators / chemical synthesis*
  • Estrogen Receptor Modulators / chemistry
  • Estrogen Receptor Modulators / pharmacology
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Female
  • HeLa Cells
  • Humans
  • Isoquinolines / chemical synthesis*
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology
  • Ligands
  • Models, Molecular
  • Radioligand Assay
  • Raloxifene Hydrochloride / chemistry
  • Raloxifene Hydrochloride / pharmacology
  • Rats
  • Receptors, Estrogen / drug effects*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Transcription, Genetic
  • Tumor Cells, Cultured

Substances

  • Estrogen Receptor Modulators
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Isoquinolines
  • Ligands
  • Receptors, Estrogen
  • Raloxifene Hydrochloride
  • Estradiol