7442-07-1Relevant articles and documents
A selective modulator of peroxisome proliferator-activated receptor γwith an unprecedented binding mode
Hanke, Thomas,Cheung, Sun-Yee,Kilu, Whitney,Heering, Jan,Ni, Xiaomin,Planz, Viktoria,Schierle, Simone,Faudone, Giuseppe,Friedrich, Marius,Wanior, Marek,Werz, Oliver,Windbergs, Maike,Proschak, Ewgenij,Schubert-Zsilavecz, Manfred,Chaikuad, Apirat,Knapp, Stefan,Merk, Daniel
, p. 4555 - 4561 (2020)
The nuclear peroxisome proliferator-activated receptor γhas well-validated therapeutic potential in metabolic, inflammatory, and neurodegenerative pathologies, but its activation is also associated with marked adverse effects and novel modes of PPARγmodulation are required. Here, we report the discovery and profiling of a new PPARγmodulator chemotype endowed with remarkable potency and a distinct binding mode in the orthosteric PPARγligand-binding site. Its R-enantiomer evolved as a eutomer regarding PPARγactivation with a high eudysmic ratio. The new PPARγmodulator revealed outstanding selectivity over the PPARα and PPARδsubtypes and did not promote adipogenesis in primary human fibroblasts, discriminating it from established agonists.
LEGO-Inspired Drug Design: Unveiling a Class of Benzo[d]thiazoles Containing a 3,4-Dihydroxyphenyl Moiety as Plasma Membrane H+-ATPase Inhibitors
Tung, Truong-Thanh,Dao, Trong T.,Junyent, Marta G.,Palmgren, Michael,Günther-Pomorski, Thomas,Fuglsang, Anja T.,Christensen, S?ren B.,Nielsen, John
, p. 37 - 47 (2018/01/12)
The fungal plasma membrane H+-ATPase (Pma1p) is a potential target for the discovery of new antifungal agents. Surprisingly, no structure–activity relationship studies for small molecules targeting Pma1p have been reported. Herein, we disclose a LEGO-inspired fragment assembly strategy for the design, synthesis, and discovery of benzo[d]thiazoles containing a 3,4-dihydroxyphenyl moiety as potential Pma1p inhibitors. A series of 2-(benzo[d]thiazol-2-ylthio)-1-(3,4-dihydroxyphenyl)ethanones was found to inhibit Pma1p, with the most potent IC50 value of 8 μm in an in vitro plasma membrane H+-ATPase assay. These compounds were also found to strongly inhibit the action of proton pumping when Pma1p was reconstituted into liposomes. 1-(3,4-Dihydroxyphenyl)-2-((6-(trifluoromethyl)benzo[d]thiazol-2-yl)thio)ethan-1-one (compound 38) showed inhibitory activities on the growth of Candida albicans and Saccharomyces cerevisiae, which could be correlated and substantiated with the ability to inhibit Pma1p in vitro.
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.
scheme or table, 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.
