893736-02-2Relevant academic research and scientific papers
Fragment-Based Discovery of 5-Arylisatin-Based Inhibitors of Matrix Metalloproteinases 2 and 13
Agamennone, Mariangela,Belov, Dmitry S.,Laghezza, Antonio,Ivanov, Vladimir N.,Novoselov, Anton M.,Andreev, Ivan A.,Ratmanova, Nina K.,Altieri, Andrea,Tortorella, Paolo,Kurkin, Alexander V.
, p. 1892 - 1898 (2016/10/06)
Matrix metalloproteinases (MMPs) are well-established targets for several pathologies. In particular, MMP-2 and MMP-13 play a prominent role in cancer progression. In this study, a structure-based screening campaign was applied to prioritize metalloproteinase-oriented fragments. This computational model was applied to a representative fragment set from the publically available EDASA Scientific compound library. These fragments were prioritized, and the top-ranking hits were tested in a biological assay to validate the model. Two scaffolds showed consistent activity in the assay, and the isatin-based compounds were the most interesting. These latter fragments have significant potential as tools for the design and realization of novel MMP inhibitors. In addition to their micromolar activity, the chemical synthesis affords flexible and creative access to their analogues.
Identification of the First Highly Subtype-Selective Inhibitor of Human GABA Transporter GAT3
Damgaard, Maria,Al-Khawaja, Anas,Vogensen, Stine B.,Jurik, Andreas,Sijm, Maarten,Lie, Maria E. K.,B?k, Mathias I.,Rosenthal, Emil,Jensen, Anders A.,Ecker, Gerhard F.,Fr?lund, Bente,Wellendorph, Petrine,Clausen, Rasmus P.
, p. 1591 - 1599 (2015/09/28)
Screening a library of small-molecule compounds using a cell line expressing human GABA transporter 3 (hGAT3) in a [3H]GABA uptake assay identified isatin derivatives as a new class of hGAT3 inhibitors. A subsequent structure-activity relationship (SAR) study led to the identification of hGAT3-selective inhibitors (i.e., compounds 20 and 34) that were superior to the reference hGAT3 inhibitor, (S)-SNAP-5114, in terms of potency (low micromolar IC50 values) and selectivity (>30-fold selective for hGAT3 over hGAT1/hGAT2/hBGT1). Further pharmacological characterization of compound 20 (5-(thiophen-2-yl)indoline-2,3-dione) revealed a noncompetitive mode of inhibition at hGAT3. This suggests that this compound class, which has no structural resemblance to GABA, has a binding site different from the substrate, GABA. This was supported by a molecular modeling study that suggested a unique binding site that matched the observed selectivity, inhibition kinetics, and SAR of the compound series. These compounds are the most potent GAT3 inhibitors reported to date that provide selectivity for GAT3 over other GABA transporter subtypes.
