117382-46-4Relevant articles and documents
Discovering Small-Molecule Estrogen Receptor α/Coactivator Binding Inhibitors: High-Throughput Screening, Ligand Development, and Models for Enhanced Potency
Sun, Aiming,Moore, Terry W.,Gunther, Jillian R.,Kim, Mi-Sun,Rhoden, Eric,Du, Yuhong,Fu, Haian,Snyder, James P.,Katzenellenbogen, John A.
, p. 654 - 666 (2012/01/05)
Small molecules, namely coactivator binding inhibitors (CBIs), that block estrogen signaling by directly inhibiting the interaction of the estrogen receptor (ER) with coactivator proteins act in a fundamentally different way to traditional antagonists, which displace the endogenous ligand estradiol. To complement our prior efforts at CBI discovery by denovo design, we used high-throughput screening (HTS) to identify CBIs of novel structure and subsequently investigated two HTS hits by analogue synthesis, finding many compounds with low micromolar potencies in cell-based reporter gene assays. We examined structure-activity trends in both series, using induced-fit computational docking to propose binding poses for these molecules in the coactivator binding groove. Analysis of the structure of the ER-steroid receptor coactivator (SRC) complex suggests that all four hydrophobic residues within the SRC nuclear receptor box sequence are important binding elements. Thus, insufficient water displacement upon binding of the smaller CBIs in the expansive complexation site may be limiting the potency of the compounds in these series, which suggests that higher potency CBIs might be found by screening compound libraries enriched with larger molecules.
Orally Bioavailable Competitive CCR5 Antagonists
Thoma, Gebhard,Nuninger, Fran?ois,Schaefer, Marc,Akyel, Kayhan G.,Albert, Rainer,Beerli, Christian,Bruns, Christian,Francotte, Eric,Luyten, Marcel,MacKenzie, Duncan,Oberer, Lukas,Streiff, Markus B.,Wagner, Trixie,Walter, Hansrudolf,Weckbecker, Gisbert,Zerwes, Hans-Guenter
, p. 1939 - 1955 (2007/10/03)
The chemokine receptor CCR5 plays an important role in inflammatory and autoimmune disorders as well as in transplant rejection by affecting the trafficking of effector T cells and monocytes to diseased tissues. Antagonists of CCR5 are believed to be of potential therapeutic value for the disorders mentioned above and HIV infection. Here we report on the structure-activity relationship of a new series of highly potent and selective competitive CCR5 antagonists. While all compounds tested were inactive on rodent CCR5, this series includes compounds that cross-react with the cynomolgus monkey (cyno) receptor. One of these compounds, i.e., 26n, has good PK properties in cynos, and its overall favorable profile makes it a promising candidate for in vivo profiling in transplantation and other disease models.
