Selective Estrogen Receptor Modulators with Conformationally Restricted Side Chains. Synthesis and Structure−Activity Relationship of ERα-Selective Tetrahydroisoquinoline Ligands

Abstract

We disclose herein the discovery of estrogen receptor alpha (ERalpha) selective estrogen receptor modulators (SERMs) of the tetrahydroisoquinoline series that incorporate novel conformationally restricted side chains as replacement of the aminoethoxy residue typical of SERMs. Molecular modeling studies used in conjunction with the X-ray crystal structure of the ERalpha ligand binding domain (LBD) with raloxifene (7) suggested a diazadecaline moiety as a viable mimic of the SERM side chain. On the basis of this knowledge, the piperidinylethoxy moiety of our lead compound 60 was replaced by a diazadecaline subunit, providing the novel tetrahydroisoquinoline 29. In addition to exhibiting a binding affinity to ERalpha and antagonistic properties in the estrogen response element and MCF-7 assays similar to those of the parent compound 60, ligand 29 showed a reduced agonist behavior in the MCF-7 assay in the absence of 17beta-estradiol. These data point toward the fact that 29 may have a potential for breast cancer prevention/treatment in vivo, a feature which is particularly attractive in the quest for safe alternatives to hormone replacement therapy. In a pharmacokinetic experiment carried out in rats, 29 displayed an interesting profile, with a bioavailability of 49%. We also disclose the X-ray crystal structure of 29 in complex with ERalpha-LBD, which reveals the preferred configurations of 29 at the two chiral centers and the details of its interactions with the receptor. Finally, our structure-activity relationship studies show that other analogues bearing constrained side chains retain potency and antagonist activity and that a 3-OH substituted phenyl D-ring increases the selectivity of a set of piperazinyl-containing ligands in favor of ERalpha over ERbeta.

Biaryl Phosphane Ligands in Palladium‐Catalyzed Amination

“…[182] BINAP gave unsatisfactorily low yields but DavePhos and SIPr carbene produced product in acceptable yields.…”

Drug Design Approaches to Manipulate the Agonist-Antagonist Equilibrium in Steroid Receptors

“…Numerous reviews of these two studies have been published Kong, Pike, and Hubbard, 2003;MuellerFahrnow and Egner, 1999; as have many further studies on the X-ray structures of SERMs, full antagonists and full agonists bound to the ERs Dykstra et al, 2007;Heldring et al, 2007;Kim et al, 2004;Renaud et al, 2003;Renaud et al, 2005;Tan et al, 2005;Vajdos et al, 2007). The same helix-12 clash has also been demonstrated for AR (Cantin et al, 2007) and GR (Schoch et al, 2010) in recent X-ray structure determination studies.…”

Tamoxifen: Catalyst for the change to targeted therapy

“…Finally, the importance of understanding the unique pharmacology of tamoxifen can be placed in perspective. In retrospect, tamoxifen could, in fact, be viewed as the lead compound that was essential to initiate the synthesis of a broad range of new SERMs for the treatment of diseases as diverse as osteoporosis (86)(87)(88)(89)(90)(91)(92) and rheumatoid arthritis (93,94) and the subsequent extrapolation of the SERM concept to all members of the nuclear receptor superfamily (76). The advances documented with targeting tamoxifen now offer the promise of designing drugs to treat diseases previously thought to be impossible.…”