title: Multistep continuous-flow synthesis in medicinal chemistry: discovery and preliminary structure-activity relationships of CCR8 ligands.
abstract: A three-step continuous-flow synthesis system and its application to the assembly of a new series of chemokine 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 sequence can be interchanged with similar outcome, extending the scope of the chemistry. Biological evaluation confirmed activity on the chemokine CCR8 receptor and provided initial structure-activity-relationship (SAR) information for this new ligand series, with the most potent member displaying 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.
authors.affiliation: Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark.
authors.forename: Trine P
authors.initials: TP
authors.lastname: Petersen
authors.forename: Sahar
authors.initials: S
authors.lastname: Mirsharghi
authors.forename: Pia C
authors.initials: PC
authors.lastname: Rummel
authors.forename: Stefanie
authors.initials: S
authors.lastname: Thiele
authors.forename: Mette M
authors.initials: MM
authors.lastname: Rosenkilde
authors.forename: Andreas
authors.initials: A
authors.lastname: Ritzén
authors.forename: Trond
authors.initials: T
authors.lastname: Ulven
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008024:Ligands; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D054401:Receptors, CCR8 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C103330:CCR8 protein, human; D007295:Inositol Phosphates; D008024:Ligands; D009281:Naphthalenes; D010879:Piperazines; D054401:Receptors, CCR8
keywords: chemokine receptor ligands; flow chemistry; medicinal chemistry; small molecule agonist; structure-activity relationships