Estrogen receptor modulators: identification and structure-activity relationships of potent ERalpha-selective tetrahydroisoquinoline ligands.
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.
Renaud
Johanne
J
Novartis Pharma Research, WKL-136.3.25, CH-4002 Basel, Switzerland. johanne.renaud@pharma.novartis.com
Bischoff
Serge François
SF
Buhl
Thomas
T
Floersheim
Philipp
P
Fournier
Brigitte
B
Halleux
Christine
C
Kallen
Joerg
J
Keller
Hansjoerg
H
Schlaeppi
Jean-Marc
JM
Stark
Wilhelm
W
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
D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D007546:Isoquinolines; D008024:Ligands; D011960:Receptors, Estrogen; D020849:Raloxifene Hydrochloride; D004958:Estradiol