Multistep Continuous-Flow Synthesis in Medicinal Chemistry: Discovery and Preliminary Structure-Activity Relationships of CCR8 Ligands

Autor:	Pia Cwarzko Rummel, Mette M. Rosenkilde, Sahar Mirsharghi, Trond Ulven, Stefanie Thiele, Andreas Ritzen, Trine P Petersen
Rok vydání:	2013
Předmět:	Agonist medicine.drug_class Stereochemistry Inositol Phosphates Naphthalenes CCR8 Ligands Medicinal chemistry Piperazines Receptors CCR8 Catalysis Structure-Activity Relationship Chlorocebus aethiops medicine Animals Humans Synthesis system Biological evaluation Continuous flow Ligand Chemistry Organic Chemistry Stereoisomerism General Chemistry Flow chemistry Combinatorial chemistry Scavenger (chemistry) COS Cells Protein Binding
Zdroj:	Petersen, T P, Mirsharghi, S, Rummel, P C, Thiele, S, Rosenkilde, M M, Ritzén, A & Ulven, T 2013, ' Multistep continuous-flow synthesis in medicinal chemistry : discovery and preliminary structure-activity relationships of CCR8 ligands ', Chemistry: A European Journal, vol. 19, no. 28, pp. 9343-9350 . https://doi.org/10.1002/chem.201204350
ISSN:	0947-6539
DOI:	10.1002/chem.201204350
Popis:	A three-step continuous-flow synthesis system and its application to the assembly of a new series of chemo- kine receptor ligands directly from commercial building blocks is reported. No scavenger columns or solvent switches are necessary to recover the desired test compounds, which were obtained in overall yields of 49-94 %. The system is modular and flexible, and the individual steps of the se- quence can be interchanged with simi- lar outcome, extending the scope of the chemistry. Biological evaluation con- firmed activity on the chemokine CCR8 receptor and provided initial structure-activity-relationship (SAR) information for this new ligand series, with the most potent member display- ing full agonist activity with single-digit nanomolar potency. To the best of our knowledge, this represents the first published example of efficient use of multistep flow synthesis combined with biological testing and SAR studies in medicinal chemistry.
Databáze:	OpenAIRE
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