Estrogen receptor modulators: identification and structure-activity relationships of potent ERalpha-selective tetrahydroisoquinoline ligands.

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Renaud J, Bischoff SF, Buhl T, Floersheim P, Fournier B, Halleux C, Kallen J, Keller H, Schlaeppi JM, Stark W

Estrogen receptor modulators: identification and structure-activity relationships of potent ERalpha-selective tetrahydroisoquinoline ligands.

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

PubMed ID
12825935 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
2-Phenyl-1-[4-(2-Piperidin-1-Yl-Ethoxy)-Phenyl]-1,2,3,4-Tetrahydro-Isoquinolin-6-OlEstrogen receptor alphaIC 50 (nM)197.422Details
2-Phenyl-1-[4-(2-Piperidin-1-Yl-Ethoxy)-Phenyl]-1,2,3,4-Tetrahydro-Isoquinolin-6-OlEstrogen receptor alphaEC 50 (nM)16.57.422Details
EstradiolEstrogen receptor alphaIC 50 (nM)287.422Details
EstradiolEstrogen receptor betaIC 50 (nM)247.422Details
RaloxifeneEstrogen receptor alphaIC 50 (nM)227.422Details
RaloxifeneEstrogen receptor alphaEC 50 (nM)2.47.422Details
RaloxifeneEstrogen receptor betaIC 50 (nM)2607.422Details
RaloxifeneEstrogen receptor betaEC 50 (nM)3417.422Details
TamoxifenEstrogen receptor alphaEC 50 (nM)6227.422Details
TamoxifenEstrogen receptor betaEC 50 (nM)>10007.422Details