Estrogen receptor ligands. Part 9: Dihydrobenzoxathiin SERAMs with alkyl substituted pyrrolidine side chains and linkers

The 2.0 Å crystal structure of the ERα ligand‐binding domain complexed with lasofoxifene

“…As in other SERM-ERa structures, the C-ring and D-ring volume of the ligand-binding pocket are filled by the phenyl side chain of lasofoxifene. The orientation of this phenyl ring is consistent with that of the tetrahydroisoquinolines, chromanes, and dihydrobenzoxathiins (Renaud et al 2003(Renaud et al , 2005Kim et al 2004;Blizzard et al 2005), but is distinct from that of the benzothiophene structure of raloxifene (Brzozowski et al 1997). The placement and orientation of this aromatic substituent in lasofoxifene forces His 524 into an alternative position (Fig.…”

“…Numerous crystal structures of ERa complexed with various SERMs have revealed a conserved mode of binding, the primary features of which involve (1) a hydrogen-bond acceptor that serves to ''anchor'' the ligand in the ERa ligandbinding pocket via a polar interaction with Arg 394; (2) a nearly planar ''core'' structure typically composed of a biaryl heterocycle, analogous to the A-ring and B-ring of 17b-estradiol; (3) a ''pendant'' side chain emanating from the ''B-ring equivalent'' of the biaryl structure (analogous to the B-ring of estradiol); and (4) a second substituent (typically aromatic) that fills the remainder (''C-ring and D-ring'' equivalent) volume of the ligand-binding pocket. A variety of SERMs with biaryl core structures have been identified in recent years, including tetrahydroisoquinolines, benzothiophenes, chromanes, and dihydrobenzoxathiins (Brzozowski et al 1997;Renaud et al 2003Renaud et al , 2005Kim et al 2004;Blizzard et al 2005;Tan et al 2005). X-ray crystal structures of representatives of each of these scaffolds illustrate the generality of the Arg 394 H-bond ''anchor'' and planar, biaryl topology features of SERM recognition ( Fig.…”

Pharmacophore and QSAR modeling of estrogen receptor β ligands and subsequent validation and in silico search for new hits

“…The structures of 119 ERb inhibitors and activators (1-119, Table A and Figure A in Supporting Information) were collected from recently published literature [2,3,6,8,9,11,16,17,[39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55]86]. Although the collected ERb ligands were gathered from different articles and were bioassayed employing two in vitro methodologies, it was possible to normalize their ERb affinities based on the fact that compound 48 and estradiol were bioassayed by the two methods.…”

Structural and chemical basis for enhanced affinity and potency for a large series of estrogen receptor ligands: 2D and 3D QSAR studies

“…The data set of 127 ERa modulators used in the QSAR analyses was selected from the literature [21][22][23][24][25][26][27][28][29][30][31]. Table 1 shows the general chemical structures of the series of ERa modulators employed in the QSAR studies.…”

“…As part of our ongoing research program aimed at discovering new selective and potent ER antagonists, and in order to investigate the quantitative structure-activity relationships (QSAR) of a large series of ERa ligands [21][22][23][24][25][26][27][28][29][30][31], we have employed the comparative molecular field analysis (CoMFA) and the hologram QSAR (HQSAR) methods to generate predictive 3D and 2D QSAR models, respectively [32,33]. The identification of key structural features responsible for binding affinity and potency should be useful for the design of novel modulators having promise of utility in clinical medicine.…”