Details

Autor(en) / Beteiligte

• Ortiz Zacarías, Natalia V
• van Veldhoven, Jacobus P. D
• den Hollander, Lisa S
• Dogan, Burak
• Openy, Joseph
• Hsiao, Ya-Yun
• Lenselink, Eelke B
• Heitman, Laura H
• IJzerman, Adriaan P

Titel

Synthesis and Pharmacological Evaluation of Triazolo­pyrimidinone Derivatives as Noncompetitive, Intracellular Antagonists for CC Chemokine Receptors 2 and 5

Ist Teil von

• Journal of medicinal chemistry, 2019-12, Vol.62 (24), p.11035-11053

Ort / Verlag

American Chemical Society

Erscheinungsjahr

2019

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• CC chemokine receptors 2 (CCR2) and 5 (CCR5) are involved in many inflammatory diseases; however, most CCR2 and CCR5 clinical candidates have been unsuccessful. (Pre)­clinical evidence suggests that dual CCR2/CCR5 inhibition might be more effective in the treatment of such multifactorial diseases. In this regard, the highly conserved intracellular binding site in chemokine receptors provides a new avenue for the design of multitarget ligands. In this study, we synthesized and evaluated the biological activity of a series of triazolo­pyrimidinone derivatives in CCR2 and CCR5. Radioligand binding assays first showed that they bind to the intracellular site of CCR2, and in combination with functional assays on CCR5, we explored structure–affinity/activity relationships in both receptors. Although most compounds were CCR2-selective, 39 and 43 inhibited β-arrestin recruitment in CCR5 with high potency. Moreover, these compounds displayed an insurmountable mechanism of inhibition in both receptors, which holds promise for improved efficacy in inflammatory diseases.