title: Estrogen receptor modulators: identification and structure-activity relationships of potent ERalpha-selective tetrahydroisoquinoline ligands.
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.
authors.affiliation: Novartis Pharma Research, WKL-136.3.25, CH-4002 Basel, Switzerland. johanne.renaud@pharma.novartis.com
authors.forename: Johanne
authors.initials: J
authors.lastname: Renaud
authors.forename: Serge François
authors.initials: SF
authors.lastname: Bischoff
authors.forename: Thomas
authors.initials: T
authors.lastname: Buhl
authors.forename: Philipp
authors.initials: P
authors.lastname: Floersheim
authors.forename: Brigitte
authors.initials: B
authors.lastname: Fournier
authors.forename: Christine
authors.initials: C
authors.lastname: Halleux
authors.forename: Joerg
authors.initials: J
authors.lastname: Kallen
authors.forename: Hansjoerg
authors.initials: H
authors.lastname: Keller
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Schlaeppi
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Stark
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D002455:Cell Division / Q000187:drug effects; D018360:Crystallography, X-Ray; D004958:Estradiol / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D011869:Radioligand Assay; D020849:Raloxifene Hydrochloride / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011960:Receptors, Estrogen / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D007546:Isoquinolines; D008024:Ligands; D011960:Receptors, Estrogen; D020849:Raloxifene Hydrochloride; D004958:Estradiol