512176-94-2Relevant academic research and scientific papers
Pyrrolone Derivatives as Intracellular Allosteric Modulators for Chemokine Receptors: Selective and Dual-Targeting Inhibitors of CC Chemokine Receptors 1 and 2
Ortiz Zacarías, Natalia V.,Van Veldhoven, Jacobus P. D.,Portner, Laura,Van Spronsen, Eric,Ullo, Salviana,Veenhuizen, Margo,Van Der Velden, Wijnand J. C.,Zweemer, Annelien J. M.,Kreekel, Roy M.,Oenema, Kenny,Lenselink, Eelke B.,Heitman, Laura H.,Ijzerman, Adriaan P.
, p. 9146 - 9161 (2018/10/24)
The recent crystal structures of CC chemokine receptors 2 and 9 (CCR2 and CCR9) have provided structural evidence for an allosteric, intracellular binding site. The high conservation of residues involved in this site suggests its presence in most chemokine receptors, including the close homologue CCR1. By using [3H]CCR2-RA-[R], a high-affinity, CCR2 intracellular ligand, we report an intracellular binding site in CCR1, where this radioligand also binds with high affinity. In addition, we report the synthesis and biological characterization of a series of pyrrolone derivatives for CCR1 and CCR2, which allowed us to identify several high-affinity intracellular ligands, including selective and potential multitarget antagonists. Evaluation of selected compounds in a functional [35S]GTPγS assay revealed that they act as inverse agonists in CCR1, providing a new manner of pharmacological modulation. Thus, this intracellular binding site enables the design of selective and multitarget inhibitors as a novel therapeutic approach.
Pyrrolidinone derivatives
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Page column 19-20, (2010/02/06)
The present invention provides pharmaceutical compositions and novel compounds useful in the treatment of conditions mediated by CCR2, MCP-1 or the interaction thereof. The compounds of the present invention are pyrrolidinones and pyrrolidine-thiones.
