1uom: Difference between revisions

==Overview==

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.

==About this Structure==

[[Category: zinc-finger]]