1008505-60-9Relevant academic research and scientific papers
Structure-Activity Relationship of Heterocyclic P2Y14Receptor Antagonists: Removal of the Zwitterionic Character with Piperidine Bioisosteres
Jung, Young-Hwan,Salmaso, Veronica,Wen, Zhiwei,Bennett, John M.,Phung, Ngan B.,Lieberman, David I.,Gopinatth, Varun,Randle, John C. R.,Chen, Zhoumou,Salvemini, Daniela,Karcz, Tadeusz P.,Cook, Donald N.,Jacobson, Kenneth A.
, p. 5099 - 5122 (2021)
A known zwitterionic, heterocyclic P2Y14R antagonist 3a was substituted with diverse groups on the central phenyl and terminal piperidine moieties, following a computational selection process. The most potent analogues contained an uncharged piperidine bioisostere, prescreened in silico, while an aza-scan (central phenyl ring) reduced P2Y14R affinity. Piperidine amide 11, 3-aminopropynyl 19, and 5-(hydroxymethyl)isoxazol-3-yl) 29 congeners in the triazole series maintained moderate receptor affinity. Adaption of 5-(hydroxymethyl)isoxazol-3-yl gave the most potent naphthalene-containing (32; MRS4654; IC50, 15 nM) and less active phenylamide-containing (33) scaffolds. Thus, a zwitterion was nonessential for receptor binding, and molecular docking and dynamics probed the hydroxymethylisoxazole interaction with extracellular loops. Also, amidomethyl ester prodrugs were explored to reversibly block the conserved carboxylate group to provide neutral analogues, which were cleavable by liver esterase, and in vivo efficacy demonstrated. We have, in stages, converted zwitterionic antagonists into neutral molecules designed to produce potent P2Y14R antagonists for in vivo application.
Design and synthesis of novel fluorescently labeled analogs of vemurafenib targeting MKK4
Kircher, Theresa,Pantsar, Tatu,Oder, Andreas,Peter von Kries, Jens,Juchum, Michael,Pfaffenrot, Bent,Kloevekorn, Philip,Albrecht, Wolfgang,Selig, Roland,Laufer, Stefan
supporting information, (2020/10/22)
The mitogen-activated protein kinase kinase 4 (MKK4) plays a key role in liver regeneration and is under investigation as a target for stimulating hepatocytes to increased proliferation. Therefore, new small molecules inhibiting MKK4 may represent a promising approach for treating acute and chronic liver diseases. Fluorescently labeled compounds are useful tools for high-throughput screenings of large compound libraries. Here we utilized the azaindole-based scaffold of FDA-approved BRAF inhibitor vemurafenib 1, which displays off-target activity on MKK4, as a starting point in our fluorescent compound design. Chemical variation of the scaffold and optimization led to a selection of fluorescent 5-TAMRA derivatives which possess high binding affinities on MKK4. Compound 45 represents a suitable tool compound for Fluorescence polarization assays to identify new small-molecule inhibitors of MKK4.
PYRIDINYLQUINAZ0LINAMINE DERIVATIVES AND THEIR USE AS B-RAF INHIBITORS
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Page/Page column 75, (2010/11/30)
The invention relates to chemical compounds of the formula (I) or pharmaceutically acceptable salts thereof, which possess B-Raf inhibitory activity and are accordingly useful for their anti cancer activity and thus in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said chemical compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of an anti-cancer effect in a warm blooded animal such as man.
